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Integrating the Neurodevelopmental and Dopamine Hypotheses of Schizophrenia and the Role of Cortical Excitation-Inhibition Balance

  • Oliver D. Howes
    Correspondence
    Address correspondence to Oliver D. Howes, M.R.C.Psych, D.M., Ph.D.
    Affiliations
    Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, United Kingdom

    Department of Psychosis, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, United Kingdom
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  • Ekaterina Shatalina
    Affiliations
    Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, United Kingdom
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Open AccessPublished:June 22, 2022DOI:https://doi.org/10.1016/j.biopsych.2022.06.017

      Abstract

      The neurodevelopmental and dopamine hypotheses are leading theories of the pathoetiology of schizophrenia, but they were developed in isolation. However, since they were originally proposed, there have been considerable advances in our understanding of the normal neurodevelopmental refinement of synapses and cortical excitation-inhibition (E/I) balance, as well as preclinical findings on the interrelationship between cortical and subcortical systems and new in vivo imaging and induced pluripotent stem cell evidence for lower synaptic density markers in patients with schizophrenia. Genetic advances show that schizophrenia is associated with variants linked to genes affecting GABA (gamma-aminobutyric acid) and glutamatergic signaling as well as neurodevelopmental processes. Moreover, in vivo studies on the effects of stress, particularly during later development, show that it leads to synaptic elimination. We review these lines of evidence as well as in vivo evidence for altered cortical E/I balance and dopaminergic dysfunction in schizophrenia. We discuss mechanisms through which frontal cortex circuitry may regulate striatal dopamine and consider how frontal E/I imbalance may cause dopaminergic dysregulation to result in psychotic symptoms.
      This integrated neurodevelopmental and dopamine hypothesis suggests that overpruning of synapses, potentially including glutamatergic inputs onto frontal cortical interneurons, disrupts the E/I balance and thus underlies cognitive and negative symptoms. It could also lead to disinhibition of excitatory projections from the frontal cortex and possibly other regions that regulate mesostriatal dopamine neurons, resulting in dopamine dysregulation and psychotic symptoms. Together, this explains a number of aspects of the epidemiology and clinical presentation of schizophrenia and identifies new targets for treatment and prevention.

      Keywords

      Schizophrenia is a common and disabling mental illness that is associated with psychotic symptoms, negative symptoms, and cognitive symptoms, such as impairments in executive function and working memory (
      • McCutcheon R.A.
      • Reis Marques T.
      • Howes O.D.
      Schizophrenia—An overview.
      ). Two key hypotheses for schizophrenia pathoetiology are the dopamine hypothesis (
      • Howes O.D.
      • Kapur S.
      The dopamine hypothesis of schizophrenia: Version III–the final common pathway.
      ) and the neurodevelopmental hypothesis (
      • Murray R.M.
      • Lewis S.W.
      Is schizophrenia a neurodevelopmental disorder?.
      ,
      • Marenco S.
      • Weinberger D.R.
      The neurodevelopmental hypothesis of schizophrenia: Following a trail of evidence from cradle to grave.
      ). The latter has recently been reframed as a sociodevelopmental hypothesis to account for the key role that psychosocial factors play in the developmental processes underlying schizophrenia (
      • Murray R.M.
      • Bhavsar V.
      • Tripoli G.
      • Howes O.
      30 years on: How the neurodevelopmental hypothesis of schizophrenia morphed into the developmental risk factor model of psychosis.
      ). These lines of thought were initially developed largely in isolation. However, recent evidence of altered excitation-inhibition (E/I) balance in schizophrenia, studies modeling synaptic pruning mechanisms, genome-wide association studies (GWASs), and novel imaging techniques localizing synaptic markers have all shown how these hypotheses may be integrated with previous work on E/I balance (
      • Grace A.A.
      Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression.
      ,
      • Insel T.R.
      Rethinking schizophrenia.
      ,
      • Lewis D.A.
      • Hashimoto T.
      • Volk D.W.
      Cortical inhibitory neurons and schizophrenia.
      ). Here, we first review normal synaptic development and evidence for neurodevelopmental abnormalities in schizophrenia before considering the evidence for E/I imbalance in schizophrenia, and then propose a new integrative hypothesis of schizophrenia that ties together the dopamine and neuro(socio)developmental theories of the disorder.

      Synaptic Dynamics During Neurodevelopment

      Studies conducted with rodents and nonhuman primates have shown that synaptic density in the brain shows marked increases early in development, followed by a period of synaptic elimination from puberty into early adulthood and then relatively stable synaptic density (
      • Drzewiecki C.M.
      • Willing J.
      • Juraska J.M.
      Synaptic number changes in the medial prefrontal cortex across adolescence in male and female rats: A role for pubertal onset.
      ,
      • Crain B.
      • Cotman C.
      • Taylor D.
      • Lynch G.
      A quantitative electron microscopic study of synaptogenesis in the dentate gyrus of the rat.
      ,
      • Zecevic N.
      • Bourgeois J.P.
      • Rakic P.
      Changes in synaptic density in motor cortex of rhesus monkey during fetal and postnatal life.
      ,
      • Rakic P.
      • Bourgeois J.P.
      • Eckenhoff M.F.
      • Zecevic N.
      • Goldman-Rakic P.S.
      Concurrent overproduction of synapses in diverse regions of the primate cerebral cortex.
      ,
      • Bourgeois J.P.
      • Rakic P.
      Changes of synaptic density in the primary visual cortex of the macaque monkey from fetal to adult stage.
      ) . Importantly, these developmental stages occur at different time points for different brain regions in a caudo-rostral manner, with the somatosensory and visual regions among the first to reach synaptic stability and the frontal cortex developing last (
      • Pinto J.G.
      • Jones D.G.
      • Murphy K.M.
      Comparing development of synaptic proteins in rat visual, somatosensory, and frontal cortex.
      ).
      Figure thumbnail gr1
      Figure 1Synaptic trajectories during normal neurodevelopment show a period of net synaptic production throughout early childhood followed by net synaptic elimination during adolescence and early adulthood, and then relatively balanced synaptic elimination and production in middle age. In schizophrenia, induced pluripotent stem cells show a failure to form as many synapses as seen in control lines early in development (equivalent to the prenatal stage). Imaging studies also report progressive gray matter volume changes in the prodrome and early phase of illness. Based on these findings, we propose that there is also aberrant synaptic formation/pruning both early and later in neurodevelopment, leading to overpruning of synapses and excitatory/inhibitory imbalance in schizophrenia. Further patient studies are required to determine the course of synaptic loss.
      Human postmortem brain samples assessed by electron microscopy (
      • Huttenlocher P.R.
      Synaptic density in human frontal cortex – developmental changes and effects of aging.
      ,
      • Petanjek Z.
      • Judaš M.
      • Šimic G.
      • Rasin M.R.
      • Uylings H.B.
      • Rakic P.
      • Kostovic I.
      Extraordinary neoteny of synaptic spines in the human prefrontal cortex.
      ) show the same temporal pattern, with peak synaptic density in the frontal cortex in early childhood followed by a gradual decline into the third decade of life (
      • Petanjek Z.
      • Judaš M.
      • Šimic G.
      • Rasin M.R.
      • Uylings H.B.
      • Rakic P.
      • Kostovic I.
      Extraordinary neoteny of synaptic spines in the human prefrontal cortex.
      ). Work comparing samples from the middle frontal gyrus to Heschl’s gyrus (auditory cortex) showed that developmental trajectories are heterochronous across regions, with frontal regions maturing later than posterior regions, similar to rodent and primate research (
      • Huttenlocher P.R.
      • Dabholkar A.S.
      Regional differences in synaptogenesis in human cerebral cortex.
      ). In line with this, synaptic developmental trajectories of the human visual cortex (V1) have been directly aligned with the V1 of rodents, with synaptic protein expression data suggesting that development continues into late childhood (
      • Pinto J.G.
      • Jones D.G.
      • Williams C.K.
      • Murphy K.M.
      Characterizing synaptic protein development in human visual cortex enables alignment of synaptic age with rat visual cortex.
      ).
      Structural magnetic resonance imaging (MRI) studies provide proxy markers that could reflect changes in synaptic density. Cortical thickness and gray matter volumes increase rapidly during childhood followed by reductions during puberty and early adolescence (
      • Shaw P.
      • Kabani N.J.
      • Lerch J.P.
      • Eckstrand K.
      • Lenroot R.
      • Gogtay N.
      • et al.
      Neurodevelopmental trajectories of the human cerebral cortex.
      ,
      • Lenroot R.K.
      • Giedd J.N.
      Brain development in children and adolescents: Insights from anatomical magnetic resonance imaging.
      ). Importantly, different brain regions differ in when gray matter markers reach their peak, start to fall, and then stabilize, with higher-order association areas such as the dorsolateral prefrontal cortex (PFC) maturing later than sensory areas (
      • Shaw P.
      • Kabani N.J.
      • Lerch J.P.
      • Eckstrand K.
      • Lenroot R.
      • Gogtay N.
      • et al.
      Neurodevelopmental trajectories of the human cerebral cortex.
      ,
      • Giorgio A.
      • Santelli L.
      • Tomassini V.
      • Bosnell R.
      • Smith S.
      • De Stefano N.
      • Johansen-Berg H.
      Age-related changes in grey and white matter structure throughout adulthood.
      ,
      • Gogtay N.
      • Giedd J.N.
      • Lusk L.
      • Hayashi K.M.
      • Greenstein D.
      • Vaituzis A.C.
      • et al.
      Dynamic mapping of human cortical development during childhood through early adulthood.
      ), thus showing the same pattern of tempororegional structural changes seen in preclinical research (
      • Lenroot R.K.
      • Giedd J.N.
      Brain development in children and adolescents: Insights from anatomical magnetic resonance imaging.
      ,
      • Giedd J.N.
      • Blumenthal J.
      • Jeffries N.O.
      • Castellanos F.X.
      • Liu H.
      • Zijdenbos A.
      • et al.
      Brain development during childhood and adolescence: A longitudinal MRI study.
      ) and human postmortem studies of synaptic measures (summarized in Figure 1) (
      • Huttenlocher P.R.
      • Dabholkar A.S.
      Regional differences in synaptogenesis in human cerebral cortex.
      ).

      Imaging Evidence for Aberrant Neurodevelopment in Schizophrenia

      Early brain development can be studied in vivo in patients using MRI techniques that measure the gyrification index, a metric that quantifies the amount of cortex buried within the sulcal fold. Formation of gyri during early brain development underlies compact wiring (
      • White T.
      • Su S.
      • Schmidt M.
      • Kao C.Y.
      • Sapiro G.
      The development of gyrification in childhood and adolescence.
      ) and is reflected in a higher gyrification index in adulthood, which has been shown to be lower in patients with schizophrenia than in control subjects (
      • Zakharova N.V.
      • Mamedova G.S.
      • Bravve L.V.
      • Kaydan M.A.
      • Syunyakov T.S.
      • Kostyuk G.P.
      • Ushakov V.L.
      Brain gyrification index in schizophrenia (review, systematic review and meta-analysis).
      ). Specifically, patients with schizophrenia have been reported to have reduced folding of the anterior cingulate cortex (
      • Zakharova N.V.
      • Mamedova G.S.
      • Bravve L.V.
      • Kaydan M.A.
      • Syunyakov T.S.
      • Kostyuk G.P.
      • Ushakov V.L.
      Brain gyrification index in schizophrenia (review, systematic review and meta-analysis).
      ,
      • Yücel M.
      • Stuart G.W.
      • Maruff P.
      • Wood S.J.
      • Savage G.R.
      • Smith D.J.
      • et al.
      Paracingulate morphologic differences in males with established schizophrenia: A magnetic resonance imaging morphometric study.
      ) and other alterations suggesting impaired gyral formation in the frontal cortex (
      • Narr K.L.
      • Thompson P.M.
      • Sharma T.
      • Moussai J.
      • Zoumalan C.
      • Rayman J.
      • Toga A.
      Three-dimensional mapping of gyral shape and cortical surface asymmetries in schizophrenia: Gender effects.
      ,
      • Vogeley K.
      • Schneider-Axmann T.
      • Pfeiffer U.
      • Tepest R.
      • Bayer T.A.
      • Bogerts B.
      • et al.
      Disturbed gyrification of the prefrontal region in male schizophrenic patients: A morphometric postmortem study.
      ). As the gyrification index is determined during early development and remains stable in adulthood (
      • White T.
      • Su S.
      • Schmidt M.
      • Kao C.Y.
      • Sapiro G.
      The development of gyrification in childhood and adolescence.
      ), these findings likely reflect early developmental abnormalities.
      Schizophrenia is also associated with lower gray matter volumes relative to control subjects, in particular in the frontal cortex, (
      • Brugger S.P.
      • Howes O.D.
      Heterogeneity and homogeneity of regional brain structure in schizophrenia: A meta-analysis.
      ,
      • Schnack H.G.
      • Van Haren N.E.
      • Nieuwenhuis M.
      • Hulshoff Pol H.E.
      • Cahn W.
      • Kahn R.S.
      Accelerated brain aging in schizophrenia: A longitudinal pattern recognition study.
      ). The progressive loss of gray matter exceeding normal age-related changes in schizophrenia indicates a neuroprogressive process, albeit one that does not result in neuronal death (
      • Vita A.
      • De Peri L.
      • Deste G.
      • Sacchetti E.
      Progressive loss of cortical gray matter in schizophrenia: A meta-analysis and meta-regression of longitudinal MRI studies [published correction appears in Transl Psychiatry. 2013;3:e275].
      ,
      • Cropley V.L.
      • Klauser P.
      • Lenroot R.K.
      • Bruggemann J.
      • Sundram S.
      • Bousman C.
      • et al.
      Accelerated gray and white matter deterioration with age in schizophrenia.
      ). Gray matter reduction in the absence of neuronal loss is consistent with the loss of synapses, but it is important to recognize that other changes could contribute to gray matter changes in schizophrenia, such as reduced neuronal processes and branching (
      • Selemon L.D.
      • Goldman-Rakic P.S.
      The reduced neuropil hypothesis: A circuit based model of schizophrenia.
      ). Further analyses found that greater gray matter loss was directly associated with greater duration of illness (
      • Haijma S.V.
      • Van Haren N.
      • Cahn W.
      • Koolschijn P.C.
      • Hulshoff Pol H.E.
      • Kahn R.S.
      Brain volumes in schizophrenia: A meta-analysis in over 18 000 subjects.
      ,
      • Olabi B.
      • Ellison-Wright I.
      • McIntosh A.M.
      • Wood S.J.
      • Bullmore E.
      • Lawrie S.M.
      Are there progressive brain changes in schizophrenia? A meta-analysis of structural magnetic resonance imaging studies.
      ), suggesting that there is at least a component of gray matter changes that occurs once the illness has developed. A number of longitudinal studies have tested this further by measuring changes in gray matter volumes over the course of illness from the first episode of psychosis (
      • Douaud G.
      • Mackay C.
      • Andersson J.
      • James S.
      • Quested D.
      • Ray M.K.
      • et al.
      Schizophrenia delays and alters maturation of the brain in adolescence.
      ). These studies have found that patients with schizophrenia show accelerated reductions in gray matter volumes in comparison to both their healthy siblings (
      • Brans R.G.
      • van Haren N.E.
      • van Baal G.C.M.
      • Schnack H.G.
      • Kahn R.S.
      • Hulshoff Pol H.E.H.
      Heritability of changes in brain volume over time in twin pairs discordant for schizophrenia.
      ) and matched healthy control subjects (
      • Brans R.G.
      • van Haren N.E.
      • van Baal G.C.M.
      • Schnack H.G.
      • Kahn R.S.
      • Hulshoff Pol H.E.H.
      Heritability of changes in brain volume over time in twin pairs discordant for schizophrenia.
      ,
      • Ho B.C.
      • Alicata D.
      • Ward J.
      • Moser D.J.
      • O’Leary D.S.
      • Arndt S.
      • Andreasen N.C.
      Untreated initial psychosis: Relation to cognitive deficits and brain morphology in first-episode schizophrenia.
      ,
      • Dietsche B.
      • Kircher T.
      • Falkenberg I.
      Structural brain changes in schizophrenia at different stages of the illness: A selective review of longitudinal magnetic resonance imaging studies.
      ). One issue with these findings is the potential role of antipsychotic treatment on gray matter changes. However, follow-up of patients that start treatment suggests that, while medication may make some contribution to gray matter reductions, an appreciable component of gray matter change is not explained by treatment (
      • Andreasen N.C.
      • Nopoulos P.
      • Magnotta V.
      • Pierson R.
      • Ziebell S.
      • Ho B.C.
      Progressive brain change in schizophrenia: A prospective longitudinal study of first-episode schizophrenia.
      ,
      • Ho B.C.
      • Andreasen N.C.
      • Ziebell S.
      • Pierson R.
      • Magnotta V.
      Long-term antipsychotic treatment and brain volumes: A longitudinal study of first-episode schizophrenia.
      ).
      Thus, taken together, the gyrification and gray matter findings suggest that schizophrenia is associated with both early and late disruption in neurodevelopment, including progressive changes during the early phase of the disorder. However, these MRI studies did not directly measure synaptic markers, so the degree to which they reflect synaptic loss or other changes in neuropil remains unclear.

      Evidence for Aberrant Synaptic Density in Schizophrenia

      Postmortem studies have investigated synaptic protein levels as well as dendritic spine densities in schizophrenia. Synaptophysin, a vesicular protein that is a widely used in vitro marker of synaptic density, has been shown to be significantly lower at the protein and messenger RNA levels in postmortem samples from patients with schizophrenia relative to healthy control subjects, specifically in the hippocampus and frontal and cingulate cortices (
      • Osimo E.F.
      • Beck K.
      • Reis Marques T.R.
      • Howes O.D.
      Synaptic loss in schizophrenia: A meta-analysis and systematic review of synaptic protein and mRNA measures.
      ). Another recent meta-analysis looking at postsynaptic density markers also identified reductions in synaptic markers in frontal regions in patients with schizophrenia relative to control subjects (
      • Berdenis van Berlekom A.
      • Muflihah C.H.
      • Snijders G.J.L.J.
      • MacGillavry H.D.
      • Middeldorp J.
      • Hol E.M.
      • et al.
      Synapse pathology in schizophrenia: A meta-analysis of postsynaptic elements in postmortem brain studies.
      ).
      Further evidence comes from in vivo work, using [11C]UCB-J PET imaging, which measures the distribution of synaptic vesicle protein 2A (SV2A). SV2A is a ubiquitously expressed synaptic vesicle protein, and thus differences in protein levels can reflect differences in synaptic density (
      • Lynch B.A.
      • Lambeng N.
      • Nocka K.
      • Kensel-Hammes P.
      • Bajjalieh S.M.
      • Matagne A.
      • Fuks B.
      The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam.
      ,
      • Finnema S.J.
      • Nabulsi N.B.
      • Mercier J.
      • Lin S.F.
      • Chen M.K.
      • Matuskey D.
      • et al.
      Kinetic evaluation and test–retest reproducibility of [11C] UCB-J, a novel radioligand for positron emission tomography imaging of synaptic vesicle glycoprotein 2A in humans.
      ). To date, 2 studies have been published comparing chronic patients with schizophrenia with control subjects. Both studies showed significantly lower SV2A density in frontal and anterior cingulate cortices in the patient groups (
      • Onwordi E.C.
      • Halff E.F.
      • Whitehurst T.
      • Mansur A.
      • Cotel M.C.
      • Wells L.
      • et al.
      Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats.
      ,
      • Radhakrishnan R.
      • Skosnik P.D.
      • Ranganathan M.
      • Naganawa M.
      • Toyonaga T.
      • Finnema S.
      • et al.
      In vivo evidence of lower synaptic vesicle density in schizophrenia.
      ). These and the postmortem studies thus provide evidence for a failure to form synapses and/or loss of synapses in the frontal cortex of patients with schizophrenia and potentially in other brain regions. Moreover, further analyses have shown that there is an altered relationship between SV2A and glutamate levels in patients with schizophrenia (
      • Onwordi E.C.
      • Whitehurst T.
      • Mansur A.
      • Statton B.
      • Berry A.
      • Quinlan M.
      • et al.
      The relationship between synaptic density marker SV2A, glutamate and N-acetyl aspartate levels in healthy volunteers and schizophrenia: A multimodal PET and magnetic resonance spectroscopy brain imaging study.
      ). Research using induced pluripotent stem cells (iPSCs) has shown reduced neuronal branching and impaired synaptic formation and increased engulfment of glutamatergic synaptosomes by microglia when the cells were cultured from patients with schizophrenia compared with those cultured from matched control subjects. (
      • Sellgren C.M.
      • Gracias J.
      • Watmuff B.
      • Biag J.D.
      • Thanos J.M.
      • Whittredge P.B.
      • et al.
      Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning.
      ,
      • Kathuria A.
      • Lopez-Lengowski K.
      • Watmuff B.
      • McPhie D.
      • Cohen B.M.
      • Karmacharya R.
      Synaptic deficits in iPSC-derived cortical interneurons in schizophrenia are mediated by NLGN2 and rescued by N-acetylcysteine.
      ,
      • Habela C.W.
      • Song H.
      • Ming G.L.
      Modeling synaptogenesis in schizophrenia and autism using human iPSC derived neurons.
      ) [for further details see (
      • Sheridan S.D.
      • Horng J.E.
      • Perlis R.H.
      Patient-derived in vitro models of microglial function and synaptic engulfment in schizophrenia.
      )]. However, it is important to note that while the data to date are consistent with a failure to form synapses and/or greater synaptic elimination, it remains to be established whether both processes or just one occurs in patients.
      These postmortem and in vivo lines of evidence indicate that altered synaptic elimination in the frontal cortex may affect excitatory (glutamatergic) synapses. However, as GABA (gamma-aminobutyric acid) was not measured in the in vivo study, further work is required to determine whether inhibitory terminals are also affected and, if so, how this compares to glutamatergic effects in vivo. In view of this, we now consider E/I balance and how it may be altered in schizophrenia.

      E/I Balance

      E/I balance refers to the relative contribution of excitatory and inhibitory synaptic inputs to brain signaling (
      • Froemke R.C.
      Plasticity of cortical excitatory-inhibitory balance.
      ). The integration of these inputs is required for effective information processing carried out by the brain and occurs at the level of individual neurons, localized neuronal circuits, and whole-brain networks. During neurodevelopment, significant shifts in E/I balance occur during a critical period for each brain region when the region is most susceptible to inputs governed by environmental factors (
      • Dorrn A.L.
      • Yuan K.
      • Barker A.J.
      • Schreiner C.E.
      • Froemke R.C.
      Developmental sensory experience balances cortical excitation and inhibition.
      ,
      • Hensch T.K.
      • Fagiolini M.
      Excitatory–inhibitory balance and critical period plasticity in developing visual cortex.
      ). The critical periods for different regions occur in a caudo-rostral manner, following a similar trajectory to synaptic markers during brain development described previously, with the frontal cortex maturing last (
      • Hensch T.K.
      • Fagiolini M.
      Excitatory–inhibitory balance and critical period plasticity in developing visual cortex.
      ,
      • Hensch T.K.
      Critical period regulation.
      ). During this time, key mechanisms are upregulated to prevent runaway signaling while achieving a high cortical signal-to-noise ratio (
      • Froemke R.C.
      Plasticity of cortical excitatory-inhibitory balance.
      ). These mechanisms include adaptation of synaptic efficacy, membrane excitability, and synapse number (
      • Froemke R.C.
      Plasticity of cortical excitatory-inhibitory balance.
      ). In particular, synaptic modification, such as pruning of excitatory synapses to increase inhibitory activity, helps prevent neural activity from back-propagating through the cell body into the dendritic tree and leading to unwanted activity (
      • Hensch T.K.
      • Fagiolini M.
      Excitatory–inhibitory balance and critical period plasticity in developing visual cortex.
      ). Paolicelli et al. (
      • Paolicelli R.C.
      • Bolasco G.
      • Pagani F.
      • Maggi L.
      • Scianni M.
      • Panzanelli P.
      • et al.
      Synaptic pruning by microglia is necessary for normal brain development.
      ) have shown that synaptic elimination is facilitated by microglia. One mechanism through which this occurs is synapses expressing a molecular tag that recruits complement proteins, identifying them as targets for engulfment by microglia (
      • Stephan A.H.
      • Barres B.A.
      • Stevens B.
      The complement system: An unexpected role in synaptic pruning during development and disease.
      ). Mice lacking complement cascade components exhibit enhanced excitatory synaptic connectivity in the mature cortex as a result of inhibited synaptic pruning (
      • Chu Y.
      • Jin X.
      • Parada I.
      • Pesic A.
      • Stevens B.
      • Barres B.
      • Prince D.A.
      Enhanced synaptic connectivity and epilepsy in C1q knockout mice.
      ), while mice overexpressing complement factor 4A (C4A) have increased synaptic engulfment by glia, reduced cortical synaptic density, and altered behavior (
      • Yilmaz M.
      • Yalcin E.
      • Presumey J.
      • Aw E.
      • Ma M.
      • Whelan C.W.
      • et al.
      Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice.
      ).

      Genetic Risk and Excitatory and Inhibitory Neurotransmission in Schizophrenia

      GWASs have shown that schizophrenia is a polygenic disorder, with multiple low-penetrance variants contributing to the genetic risk for the disorder (
      • McCutcheon R.A.
      • Reis Marques T.
      • Howes O.D.
      Schizophrenia—An overview.
      ). One of the most significant genetic associations with schizophrenia implicates genes of the major histocompatibility locus encoding adaptive immune system components. This arises in part from the presence of many structurally diverse alleles of a complement protein, C4A, which tags synapses for elimination by microglia (
      • Sekar A.
      • Bialas A.R.
      • De Rivera H.
      • Davis A.
      • Hammond T.R.
      • Kamitaki N.
      • et al.
      Schizophrenia risk from complex variation of complement component 4.
      ). In addition, several other genes with roles in microglia-mediated pruning have been identified in GWASs (Table 1). Many of the other loci associated with schizophrenia encode excitatory and inhibitory neurotransmission components or play a role in establishing E/I balance during neurodevelopment as summarized in Table 1 and with further detail in Table S1.
      Table 1Loci Associated With Schizophrenia Identified by Genome-wide Association Studies (GWASs) That Have a Functional Role in Excitatory and Inhibitory Signaling or Synaptic Pruning
      GeneProtein and Functional Role
      Genes for Proteins Involved in Excitatory Neurotransmission
      ADAM10ADAM metallopeptidase domain 10 (ADAM10) is a metalloprotease involved upstream of the pathway leading to synapse elimination by microglia. It is trafficked and is functional at the excitatory synapse membrane.
      AKT3AKT serine/threonine kinase 3, AKT activity shown to inhibit metabotropic glutamate receptor (mGluR) mediated long-term depression, plays a role in synaptic plasticity in the hippocampus
      CACNA1Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents
      CACNA1DL-type voltage-gated calcium channel α-1D subunit
      CACNA1Calcium voltage-gated channel subunit alpha1 I, T-type calcium channel subunit, involved in neuronal calcium signaling
      CACNB2Voltage-dependent L-type calcium channel subunit beta-2, component of a calcium channel complex, involved in neuronal calcium signaling
      DLG2Discs large MAGUK scaffold protein 2 (DLG2) is part of the postsynaptic protein scaffold of excitatory synapses and is involved in NMDA signaling.
      FLOT1Flotillin-1 (FLOT1) enhances the formation of glutamatergic synapses but not GABAergic synapses. Flot1 has been shown to be essential for amphetamine-induced reverse transport of DA in neurons but not for DA uptake.
      GRIA1Glutamate ionotropic receptor AMPA type subunit 1
      GRIN2AGlutamate ionotropic receptor NMDA type subunit 2A
      GRM3Glutamate metabotropic receptor 3
      HCN1The hyperpolarization-activated cyclic nucleotide-gated (HCN1) channels modulate the rate of glutamate release by changing rate of exocytosis in synaptic terminals.
      RYR3Ryanodine receptor type 3 (RyR3) involved in Ca signaling
      SRRSerine racemase catalyzes the synthesis of D-serine from L-serine. D-serine is a key coagonist with glutamate at NMDA receptors.
      SYNGAP1Synaptic ras GTPase activating protein 1 (SYNGAP1) is a member of the NMDAR signaling complex in excitatory synapses and may play a role in NMDAR-dependent control of AMPAR potentiation, AMPAR membrane trafficking, and synaptic plasticity.
      Genes for Proteins Involved in Inhibitory Neurotransmission
      ANK3Ankyrin-G/ankyrin-3 (ANK3) is integral to AMPAR-mediated synaptic transmission and maintenance of spine morphology. It promotes stability of somatodendritic GABAergic synapses in vitro and in vivo through opposing endocytosis of GABAA receptors.
      CLCN3Chloride voltage-gated channel 3 plays a role in inhibitory transmission via neurotransmitter loading of synaptic vesicles dependent on vesicular acidification. Cl in inhibitory transmission may be both postsynaptic permeant species and a presynaptic regulatory element.
      FURINFurin, a protease enzyme, is involved in GABAA-mediated synaptic transmission.
      GABBR1γ-aminobutyric acid type B receptor subunit 1
      GABBR2γ-aminobutyric acid type B receptor subunit 2
      PLCL1Phospholipase C like 1 regulates the turnover of GABAA receptors via phospho-dependent endocytosis and thus contributes to the maintenance of GABA-mediated synaptic inhibition.
      SLC32A1Solute carrier family 32 member 1 is involved in the uptake of GABA and glycine into the synaptic vesicles.
      Microglial Genes With a Known Function in Synaptic Pruning
      ADAM10ADAM metallopeptidase domain 10 (ADAM10) is a metalloprotease involved upstream of the pathway leading to synapse elimination by microglia. It is trafficked and is functional at the excitatory synapse membrane.
      CSMD1Regulator of C4 expression
      C4Complement component 4, protein expressed on synapses to tag them for elimination by microglia
      PDE4BPhosphodiesterase 4B is a microglia target to reduce neuroinflammation, also expressed at the synapse.
      VRK2Vaccinia-related kinase 2 plays a critical role in microglia-mediated synapse elimination during neurodevelopment.
      Genes for Proteins Involved in Establishing E/I Balance During Neurodevelopment
      AMBRA1Autophagy and beclin 1 regulator 1 (Ambra1) is implicated in neurodevelopment, playing a key role in the maturation of hippocampal parvalbumin interneurons and thus in maintaining a proper excitation/inhibition balance in the brain.
      CLSTN3Calsyntenin-3 promotes inhibitory and excitatory synaptic development.
      CUL3Culin-3 is compartmentalized at postsynaptic densities and gates retrograde signaling; it is involved in neural development, neurotransmission, and maintaining E/I balance and glutamate receptor turnover.
      FOXP1Forkhead box protein 1 is a transcription factor for genes associated with synaptic function and development.
      GPM6AGlycoprotein M6A contributes to spine and, likely, synapse formation.
      HIP1RHuntingtin-interacting protein 1-related protein plays a critical role in dendritic development and excitatory synapse formation in hippocampal neurons.
      IGSF9BImmunoglobulin superfamily member 9B is a transmembrane protein which is abundantly expressed in interneurons, where it may regulate inhibitory synapse development.
      KALRNKalirin7 is involved in the formation of dendritic spines.
      LRRTM4Leucine rich repeat transmembrane neuronal 4 is involved in regulating excitatory synapse development.
      MEF2CMyocyte enhancer factor 2C plays a role in hippocampal-dependent learning and memory by suppressing the number of excitatory synapses and thus regulating basal and evoked synaptic transmission. Crucial for normal neuronal development, distribution, and electrical activity in the neocortex
      NLGN4XNeuroligin 4 X-linked is a member of the neuroligin family of proteins, which are involved in the regulation of excitatory synaptic transmission.
      AMPAR, AMPA receptor; DA, dopamine; E/I, excitation-inhibition; GABA, gamma-aminobutyric acid; NMDAR, NMDA receptor.
      Key loci associated with schizophrenia risk linked to excitatory neurotransmission include components of the NMDA receptor (NMDAR) (subunit 2A), the AMPA receptor (glutamate receptor 1), and the metabotropic glutamate receptor 3 (GRM3) genes (
      • Ikeda M.
      • Takahashi A.
      • Kamatani Y.
      • Momozawa Y.
      • Saito T.
      • Kondo K.
      • et al.
      Genome-wide association study detected novel susceptibility genes for schizophrenia and shared trans-populations/diseases genetic effect.
      ). They also include loci encoding channel components affecting membrane excitability, enzyme serine racemase, which catalyzes synthesis of the glutamate co-agonist D-serine, as well as genes encoding components of the postsynaptic protein scaffold of excitatory synapses including postsynaptic density protein 93 (PSD-93) and SYNGAP1, which is thought to be involved in NMDAR-dependent control of AMPA receptor potentiation (
      • Ikeda M.
      • Takahashi A.
      • Kamatani Y.
      • Momozawa Y.
      • Saito T.
      • Kondo K.
      • et al.
      Genome-wide association study detected novel susceptibility genes for schizophrenia and shared trans-populations/diseases genetic effect.
      ,
      • Paul A.
      • Nawalpuri B.
      • Shah D.
      • Sateesh S.
      • Muddashetty R.S.
      • Clement J.P.
      Differential regulation of Syngap1 translation by FMRP modulates eEF2 mediated response on NMDAR activity.
      ).
      Schizophrenia-associated loci encoding proteins involved in inhibitory neurotransmission include GABAB receptor components GABBR1 and GABBR2 (
      • Ikeda M.
      • Takahashi A.
      • Kamatani Y.
      • Momozawa Y.
      • Saito T.
      • Kondo K.
      • et al.
      Genome-wide association study detected novel susceptibility genes for schizophrenia and shared trans-populations/diseases genetic effect.
      ,
      • Yu H.
      • Yan H.
      • Li J.
      • Li Z.
      • Zhang X.
      • Ma Y.
      • et al.
      Common variants on 2p16.1, 6p22.1 and 10q24. 32 are associated with schizophrenia in Han Chinese population.
      ) and loci linked to proteins that mediate GABA receptor turnover such as ankyrin-G (ANK3), which promotes stability of somatodendritic GABAergic synapses (
      • Ikeda M.
      • Takahashi A.
      • Kamatani Y.
      • Momozawa Y.
      • Saito T.
      • Kondo K.
      • et al.
      Genome-wide association study detected novel susceptibility genes for schizophrenia and shared trans-populations/diseases genetic effect.
      ,
      Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium
      Genome-wide association study identifies five new schizophrenia loci.
      ,
      • Bergen S.E.
      • O’dushlaine C.T.
      • Ripke S.
      • Lee P.H.
      • Ruderfer D.M.
      • Akterin S.
      • et al.
      Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder.
      ). Furin, a protein involved in GABAergic transmission, also influences expression of GABAA receptor components and has been implicated in schizophrenia GWASs along with CLCN3 and SLC32A1 (encoding the vesicular GABA transporter), both of which are involved in controlling GABA uptake into synaptic vesicles (
      • Ikeda M.
      • Takahashi A.
      • Kamatani Y.
      • Momozawa Y.
      • Saito T.
      • Kondo K.
      • et al.
      Genome-wide association study detected novel susceptibility genes for schizophrenia and shared trans-populations/diseases genetic effect.
      ,
      Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium
      Genome-wide association study identifies five new schizophrenia loci.
      ,
      • Yang Y.
      • He M.
      • Tian X.
      • Guo Y.
      • Liu F.
      • Li Y.
      • et al.
      Transgenic overexpression of furin increases epileptic susceptibility.
      ,
      • Riazanski V.
      • Deriy L.V.
      • Shevchenko P.D.
      • Le B.
      • Gomez E.A.
      • Nelson D.J.
      Presynaptic CLC-3 determines quantal size of inhibitory transmission in the hippocampus.
      ).
      These findings, summarized in Figure 2, indicate that genetic risk for schizophrenia affects proteins involved in both excitatory and inhibitory signaling, which together could predispose an individual to E/I imbalance, although the direction of the imbalance cannot be inferred based on genetic data alone. This imbalance could occur through effects on homeostatic synaptic scaling or during initial circuit formation, given that risk loci encoding neurodevelopmental genes contributing to E/I balance during circuit formation have also been identified (Table 1). One caveat is that many variants associated with schizophrenia also occur outside coding regions (
      • Barešić A.
      • Nash A.J.
      • Dahoun T.
      • Howes O.
      • Lenhard B.
      Understanding the genetics of neuropsychiatric disorders: The potential role of genomic regulatory blocks.
      ). Their effects and those of other risk variants on E/I balance remain to be investigated. Key future experiments include iPSC models, where a variant can be knocked down in the presence of a schizophrenia genetic background, or animal models similar to those that have clarified the genetic effects of high-penetrance variants such as the 22q11.2 deletion on E/I balance in schizophrenia (
      • Amin H.
      • Marinaro F.
      • Tonelli D.D.P.
      • Berdondini L.
      Developmental excitatory-to-inhibitory GABA-polarity switch is disrupted in 22q11. 2 deletion syndrome: A potential target for clinical therapeutics.
      ). Importantly, effects need to be considered at the systems level because they may vary by circuit and depend on the state of the rest of the system. In view of this, we next review in vivo evidence for E/I imbalance at the whole-brain level in patients with schizophrenia.
      Figure thumbnail gr2
      Figure 2Genes encoding inhibitory and excitatory signaling components identified by schizophrenia genome-wide association studies associated with schizophrenia risk. AKT3, AKT serine/threonine kinase 3; ANK3, ankyrin-G/ankyrin-3; CACNA1, voltage-gated calcium channel subunit alpha1; CACNB2, voltage-dependent L-type calcium channel subunit beta-2; CLCN3, chloride voltage-gated channel 3; DLG2, discs large MAGUK scaffold protein 2; GABBR, γ-aminobutyric acid type B receptor; GRIN2A, glutamate ionotropic receptor NMDA type subunit 2A; GRIA1, glutamate ionotropic receptor AMPA type subunit 1; GRM3, glutamate metabotropic receptor 3; HCN1, hyperpolarization-activated cyclic nucleotide-gated channel component; PLCL1, phospholipase C like 1; SLC32A1, solute carrier family 32 member 1; SRR, serine racemase; SYNGAP1, synaptic Ras GTPase activating protein 1.

      In Vivo Evidence for Altered E/I Balance in Schizophrenia

      Electroencephalography (EEG) and magnetoencephalography techniques provide measures of neural responses mediated by GABAergic and glutamatergic systems (
      • Uhlhaas P.J.
      • Singer W.
      Oscillations and neuronal dynamics in schizophrenia: The search for basic symptoms and translational opportunities.
      ). Typically, patients are reported to have elevated gamma power at rest, thought to be due to impaired GABA signaling (
      • Bianciardi B.
      • Uhlhaas P.J.
      Do NMDA-R antagonists re-create patterns of spontaneous gamma-band activity in schizophrenia? A systematic review and perspective.
      ,
      • Reilly T.J.
      • Nottage J.F.
      • Studerus E.
      • Rutigliano G.
      • Micheli A.I.D.
      • Fusar-Poli P.
      • McGuire P.
      Gamma band oscillations in the early phase of psychosis: A systematic review.
      ,
      • Grent-’t-Jong T.
      • Gross J.
      • Goense J.
      • Wibral M.
      • Gajwani R.
      • Gumley A.I.
      • et al.
      Resting-state gamma-band power alterations in schizophrenia reveal E/I-balance abnormalities across illness-stages.
      ). They also have sensory gating deficits, specifically, impaired suppression of the P50 early event-related potential, which is mediated through GABAB receptors that are located on glutamatergic afferents and that inhibit pyramidal neuron firing (
      • De Wilde O.M.
      • Bour L.J.
      • Dingemans P.M.
      • Koelman J.H.
      • Linszen D.H.
      A meta-analysis of P50 studies in patients with schizophrenia and relatives: Differences in methodology between research groups.
      ,
      • Daskalakis Z.J.
      • Fitzgerald P.B.
      • Christensen B.K.
      The role of cortical inhibition in the pathophysiology and treatment of schizophrenia.
      ,
      • Freedman R.
      • Adams C.E.
      • Adler L.E.
      • Bickford P.C.
      • Gault J.
      • Harris J.G.
      • et al.
      Inhibitory neurophysiological deficit as a phenotype for genetic investigation of schizophrenia.
      ). The combination of transcranial magnetic stimulation with EEG provides another method of probing changes in GABAA, GABAB, and NMDA-mediated activity using paradigms such as short-interval intracortical inhibition, long-interval intracortical inhibition, and intracortical facilitation, respectively (
      • Cash R.F.
      • Noda Y.
      • Zomorrodi R.
      • Radhu N.
      • Farzan F.
      • Rajji T.K.
      • et al.
      Characterization of glutamatergic and GABAA-mediated neurotransmission in motor and dorsolateral prefrontal cortex using paired-pulse TMS–EEG.
      ) (additional details in the Supplement). These responses have been shown to be reduced in patients with schizophrenia in comparison to control subjects (
      • Li X.
      • Honda S.
      • Nakajima S.
      • Wada M.
      • Yoshida K.
      • Daskalakis Z.J.
      • et al.
      TMS-EEG research to elucidate the pathophysiological neural bases in patients with schizophrenia: A systematic review.
      ). Another measure, the mismatch negativity response, is dependent on intact NMDAR signaling (
      • Garrido M.I.
      • Kilner J.M.
      • Stephan K.E.
      • Friston K.J.
      The mismatch negativity: A review of underlying mechanisms.
      ,
      • Umbricht D.
      • Koller R.
      • Vollenweider F.X.
      • Schmid L.
      Mismatch negativity predicts psychotic experiences induced by NMDA receptor antagonist in healthy volunteers.
      ). Results of a meta-analysis have shown that the mismatch negativity response is lower in patients with schizophrenia than in healthy control subjects, with a large effect size (
      • Erickson M.A.
      • Ruffle A.
      • Gold J.M.
      A meta-analysis of mismatch negativity in schizophrenia: From clinical risk to disease specificity and progression.
      ) and with a recent study showing that reduced mismatch negativity response amplitude was associated with reduced glutamate levels measured with magnetic resonance spectroscopy in this patient group (
      • Rowland L.M.
      • Summerfelt A.
      • Wijtenburg S.A.
      • Du X.
      • Chiappelli J.J.
      • Krishna N.
      • et al.
      Frontal glutamate and gamma-aminobutyric acid levels and their associations with mismatch negativity and digit sequencing task performance in schizophrenia.
      ). This is consistent with findings of lower NMDAR levels in schizophrenia (
      • Beck K.
      • Arumuham A.
      • Veronese M.
      • Santangelo B.
      • McGinnity C.J.
      • Dunn J.
      • et al.
      N-methyl-D-aspartate receptor availability in first-episode psychosis: A PET-MR brain imaging study.
      ). Notwithstanding this, postmortem studies show lower levels of GABAergic markers in cortical brain regions (
      • Kaar S.J.
      • Natesan S.
      • McCutcheon R.
      • Howes O.D.
      Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology.
      ). While the previously mentioned studies all indicate an E/I imbalance, they do not infer the location and direction of the shift and may be confounded by the effects of medication on magnetoencephalography/EEG signal. Computational modeling of EEG data from schizophrenia patients suggests that deficits are best explained by primary loss of synaptic gain on pyramidal cells that is then compensated by interneuron downregulation (
      • Adams R.A.
      • Pinotsis D.
      • Tsirlis K.
      • Unruh L.
      • Mahajan A.
      • Horas A.M.
      • et al.
      Computational modeling of electroencephalography and functional magnetic resonance imaging paradigms indicates a consistent loss of pyramidal cell synaptic gain in schizophrenia.
      ).
      These findings are consistent with altered E/I balance in schizophrenia and have been linked with cognitive symptoms including impaired executive function (
      • Calvin O.L.
      • Redish A.D.
      Global disruption in excitation-inhibition balance can cause localized network dysfunction and Schizophrenia-like context-integration deficits.
      ). Both altered gamma oscillatory activity (
      • Uhlhaas P.J.
      • Singer W.
      Oscillations and neuronal dynamics in schizophrenia: The search for basic symptoms and translational opportunities.
      ,
      • Gonzalez-Burgos G.
      • Cho R.Y.
      • Lewis D.A.
      Alterations in cortical network oscillations and parvalbumin neurons in schizophrenia.
      ) and dorsolateral prefrontal cortical short-interval intracortical inhibition responses are correlated with cognitive function in schizophrenia (
      • Noda Y.
      • Barr M.S.
      • Zomorrodi R.
      • Cash R.F.H.
      • Farzan F.
      • Rajji T.K.
      • et al.
      Evaluation of short interval cortical inhibition and intracortical facilitation from the dorsolateral prefrontal cortex in patients with schizophrenia.
      ). Recent work has also shown working memory deficits following administration of ketamine, a NMDAR antagonist, to nonhuman primates. These resembled deficits seen in schizophrenia and were accompanied by decreased inhibitory interneuron and increased excitatory activity in the lateral PFC (
      • Roussy M.
      • Luna R.
      • Duong L.
      • Corrigan B.
      • Gulli R.A.
      • Nogueira R.
      • et al.
      Ketamine disrupts naturalistic coding of working memory in primate lateral prefrontal cortex networks.
      ). Thus, these findings indicate that E/I imbalance could underlie cognitive impairments in schizophrenia. In the following sections we consider the key question of how these cortical impairments may also lead to psychotic symptoms.

      Dopamine Abnormalities in Schizophrenia

      Multiple lines of evidence from genetic, postmortem, and pharmacological studies support the hypothesis that dopamine dysregulation plays a central role in the development of schizophrenia (
      • Howes O.D.
      • Murray R.M.
      Schizophrenia: An integrated sociodevelopmental-cognitive model.
      ,
      • McCutcheon R.A.
      • Krystal J.H.
      • Howes O.D.
      Dopamine and glutamate in schizophrenia: Biology, symptoms and treatment.
      ,
      • Carlsson A.
      Does dopamine have a role in schizophrenia?.
      ). Notably, all currently licensed antipsychotics are dopamine D2/D3 receptor blockers (
      • Kaar S.J.
      • Natesan S.
      • McCutcheon R.
      • Howes O.D.
      Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology.
      ). Moreover, molecular imaging techniques have found significant elevations in striatal dopamine synthesis and release capacity in vivo in patients with schizophrenia, with large effect sizes (
      • Brugger S.P.
      • Angelescu I.
      • Abi-Dargham A.
      • Mizrahi R.
      • Shahrezaei V.
      • Howes O.D.
      Heterogeneity of striatal dopamine function in schizophrenia: Meta-analysis of variance.
      ,
      • Howes O.D.
      • Kambeitz J.
      • Kim E.
      • Stahl D.
      • Slifstein M.
      • Abi-Dargham A.
      • Kapur S.
      The nature of dopamine dysfunction in schizophrenia and what this means for treatment.
      ,
      • McCutcheon R.
      • Beck K.
      • Jauhar S.
      • Howes O.D.
      Defining the locus of dopaminergic dysfunction in schizophrenia: A meta-analysis and test of the mesolimbic hypothesis.
      ,
      • Laruelle M.
      • Abi-Dargham A.
      • Van Dyck C.H.
      • Gil R.
      • D’Souza C.D.
      • Erdos J.
      • et al.
      Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects.
      ,
      • Breier A.
      • Su T.P.
      • Saunders R.
      • Carson R.E.
      • Kolachana B.S.
      • De Bartolomeis A.
      • et al.
      Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: Evidence from a novel positron emission tomography method.
      ,
      • Abi-Dargham A.
      • Rodenhiser J.
      • Printz D.
      • Zea-Ponce Y.
      • Gil R.
      • Kegeles L.S.
      • et al.
      Increased baseline occupancy of D2 receptors by dopamine in schizophrenia.
      ). Moreover, meta-analysis has shown that the largest increases are seen in parts of the striatum that are highly innervated by projections from the frontal cortex (
      • McCutcheon R.
      • Beck K.
      • Jauhar S.
      • Howes O.D.
      Defining the locus of dopaminergic dysfunction in schizophrenia: A meta-analysis and test of the mesolimbic hypothesis.
      ,
      • Howes O.D.
      • Montgomery A.J.
      • Asselin M.C.
      • Murray R.M.
      • Valli I.
      • Tabraham P.
      • et al.
      Elevated striatal dopamine function linked to prodromal signs of schizophrenia.
      ,
      • Kegeles L.S.
      • Abi-Dargham A.
      • Frankle W.G.
      • Gil R.
      • Cooper T.B.
      • Slifstein M.
      • et al.
      Increased synaptic dopamine function in associative regions of the striatum in schizophrenia.
      ), and greater dopamine synthesis capacity in this region is directly associated with more severe psychotic symptoms (
      • Jauhar S.
      • Nour M.M.
      • Veronese M.
      • Rogdaki M.
      • Bonoldi I.
      • Azis M.
      • et al.
      A test of the transdiagnostic dopamine hypothesis of psychosis using positron emission tomographic imaging in bipolar affective disorder and schizophrenia.
      ,
      • Jauhar S.
      • Veronese M.
      • Nour M.M.
      • Rogdaki M.
      • Hathway P.
      • Turkheimer F.E.
      • et al.
      Determinants of treatment response in first-episode psychosis: An 18 F-DOPA PET study.
      ). In contrast, striatal regions that are innervated by limbic areas show much less marked changes on average (
      • McCutcheon R.
      • Beck K.
      • Jauhar S.
      • Howes O.D.
      Defining the locus of dopaminergic dysfunction in schizophrenia: A meta-analysis and test of the mesolimbic hypothesis.
      ).
      Elevated striatal dopamine synthesis and release capacity has also been found in people at genetic and/or clinical high risk for schizophrenia in some studies (
      • Howes O.D.
      • Montgomery A.J.
      • Asselin M.C.
      • Murray R.M.
      • Valli I.
      • Tabraham P.
      • et al.
      Elevated striatal dopamine function linked to prodromal signs of schizophrenia.
      ,
      • Rogdaki M.
      • Devroye C.
      • Ciampoli M.
      • Veronese M.
      • Ashok A.H.
      • McCutcheon R.A.
      • et al.
      Striatal dopaminergic alterations in individuals with copy number variants at the 22q11. 2 Genetic locus and their implications for psychosis risk: A [18F]-DOPA PET study.
      ,
      • Mizrahi R.
      • Addington J.
      • Rusjan P.M.
      • Suridjan I.
      • Ng A.
      • Boileau I.
      • et al.
      Increased stress-induced dopamine release in psychosis.
      ) although not in all, potentially because not all patients are actually in the prodrome to schizophrenia (
      • McCutcheon R.A.
      • Merritt K.
      • Howes O.D.
      Dopamine and glutamate in individuals at high risk for psychosis: A meta-analysis of in vivo imaging findings and their variability compared to controls.
      ). Notwithstanding this issue, dopaminergic elevations were most marked in striatal regions innervated by frontal cortical projections, as with schizophrenia, and greater elevation here is associated with more severe prodromal-type symptoms (
      • Howes O.D.
      • Kambeitz J.
      • Kim E.
      • Stahl D.
      • Slifstein M.
      • Abi-Dargham A.
      • Kapur S.
      The nature of dopamine dysfunction in schizophrenia and what this means for treatment.
      ,
      • Howes O.D.
      • Bonoldi I.
      • McCutcheon R.A.
      • Azis M.
      • Antoniades M.
      • Bossong M.
      • et al.
      Glutamatergic and dopaminergic function and the relationship to outcome in people at clinical high risk of psychosis: A multi-modal PET-magnetic resonance brain imaging study.
      ).

      Evidence Cortical Disruption Leads to Striatal Dopamine Overactivity

      Several lines of preclinical and clinical evidence indicate that the activity of mesostriatal dopaminergic neurons is regulated by cortical projections, specifically from the frontal cortex. Lesions of the frontal cortex lead to increased striatal dopamine levels in rats (
      • Pycock C.J.
      • Carter C.J.
      • Kerwin R.W.
      Effect of 6-hydroxydopamine lesions of the medial prefrontal cortex on neurotransmitter systems in subcortical sites in the rat.
      ,
      • Pycock C.J.
      • Kerwin R.W.
      • Carter C.J.
      Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats.
      ). More recent work shows that applying electrical and optogenetic stimulation to the medial PFC results in striatal dopamine release both directly through excitatory afferents (
      • Quiroz C.
      • Orrú M.
      • Rea W.
      • Ciudad-Roberts A.
      • Yepes G.
      • Britt J.P.
      • Ferré S.
      Local control of extracellular dopamine levels in the medial nucleus accumbens by a glutamatergic projection from the infralimbic cortex.
      ) and indirectly through further activation of cholinergic and glutamatergic systems (
      • Quiroz C.
      • Orrú M.
      • Rea W.
      • Ciudad-Roberts A.
      • Yepes G.
      • Britt J.P.
      • Ferré S.
      Local control of extracellular dopamine levels in the medial nucleus accumbens by a glutamatergic projection from the infralimbic cortex.
      ,
      • Adrover M.F.
      • Shin J.H.
      • Quiroz C.
      • Ferré S.
      • Lemos J.C.
      • Alvarez V.A.
      Prefrontal cortex-driven dopamine signals in the striatum show unique spatial and pharmacological properties.
      ). Evidence that synaptic changes might be involved comes from a mouse model that leads to the loss of synapses onto excitatory neurons in the frontal cortex (
      • Kim I.H.
      • Rossi M.A.
      • Aryal D.K.
      • Racz B.
      • Kim N.
      • Uezu A.
      • et al.
      Spine pruning drives antipsychotic-sensitive locomotion via circuit control of striatal dopamine.
      ). Progressive spine loss in this model led to increased striatal dopamine levels comparable to those from optogenetic simulation of circuitry connecting the frontal cortex with the ventral tegmental area/substantia nigra pars compacta (
      • Kim I.H.
      • Rossi M.A.
      • Aryal D.K.
      • Racz B.
      • Kim N.
      • Uezu A.
      • et al.
      Spine pruning drives antipsychotic-sensitive locomotion via circuit control of striatal dopamine.
      ). This study also showed that both frontal optogenetic stimulation and progressive cortical synaptic loss lead to hyperlocomotion as well as to increased striatal dopamine (
      • Kim I.H.
      • Rossi M.A.
      • Aryal D.K.
      • Racz B.
      • Kim N.
      • Uezu A.
      • et al.
      Spine pruning drives antipsychotic-sensitive locomotion via circuit control of striatal dopamine.
      ).
      NMDAR antagonists such as ketamine cause negative, cognitive, and positive symptoms in healthy volunteers and worsen symptoms in patients with schizophrenia (
      • Beck K.
      • Hindley G.
      • Borgan F.
      • Ginestet C.
      • McCutcheon R.
      • Brugger S.
      • et al.
      Association of ketamine with psychiatric symptoms and implications for its therapeutic use and for understanding schizophrenia: A systematic review and meta-analysis.
      ). Mice treated with subchronic ketamine present with hyperlocomotion, locomotor sensitization, and increased striatal dopamine synthesis capacity (
      • Kokkinou M.
      • Irvine E.E.
      • Bonsall D.R.
      • Natesan S.
      • Wells L.A.
      • Smith M.
      • et al.
      Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: A translational imaging study with ketamine.
      ). Moreover, this effect is dependent on midbrain dopamine neuron firing and can be prevented by activating inhibitory interneurons in cortical regions, highlighting that cortical E/I balance influences subcortical dopamine neuron function (
      • Kokkinou M.
      • Irvine E.E.
      • Bonsall D.R.
      • Natesan S.
      • Wells L.A.
      • Smith M.
      • et al.
      Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: A translational imaging study with ketamine.
      ). Subchronic ketamine administration is also associated with elevated resting gamma power (
      • Bianciardi B.
      • Uhlhaas P.J.
      Do NMDA-R antagonists re-create patterns of spontaneous gamma-band activity in schizophrenia? A systematic review and perspective.
      ), as seen in schizophrenia (see above). This effect of ketamine was partially rescued through tonic inhibition of the basal forebrain, further highlighting the potential role of E/I balance (
      • McNally J.M.
      • Aguilar D.D.
      • Katsuki F.
      • Radzik L.K.
      • Schiffino F.L.
      • Uygun D.S.
      • et al.
      Optogenetic manipulation of an ascending arousal system tunes cortical broadband gamma power and reveals functional deficits relevant to schizophrenia.
      ).
      In healthy control subjects, a single dose of ketamine increases amphetamine-induced striatal dopamine release (
      • Kegeles L.S.
      • Abi-Dargham A.
      • Zea-Ponce Y.
      • Rodenhiser-Hill J.
      • Mann J.J.
      • Van Heertum R.L.
      • et al.
      Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: Implications for schizophrenia.
      ), which mimics the higher dopamine release to an amphetamine challenge in schizophrenia. Data from patient studies also show a potential link between frontal cortical measures and striatal dopamine function. For example, striatal dopamine synthesis capacity was shown to be negatively correlated with prefrontal gray matter volume in patients with schizophrenia (
      • D’Ambrosio E.
      • Jauhar S.
      • Kim S.
      • Veronese M.
      • Rogdaki M.
      • Pepper F.
      • et al.
      The relationship between grey matter volume and striatal dopamine function in psychosis: A multimodal 18F-DOPA PET and voxel-based morphometry study.
      ). Furthermore, lower N-acetylaspartate levels in the dorsolateral PFC were associated with greater amphetamine-induced release of striatal dopamine in patients with schizophrenia, but not in healthy control subjects (
      • Bertolino A.
      • Breier A.
      • Callicott J.H.
      • Adler C.
      • Mattay V.S.
      • Shapiro M.
      • et al.
      The relationship between dorsolateral prefrontal neuronal N-acetylaspartate and evoked release of striatal dopamine in schizophrenia.
      ). As lower N-acetylaspartate levels are associated with neuronal dysfunction (
      • Whitehurst T.S.
      • Osugo M.
      • Townsend L.
      • Shatalina E.
      • Vava R.
      • Onwordi E.C.
      • Howes O.
      Proton magnetic resonance spectroscopy of N-acetyl aspartate in chronic schizophrenia, first episode of psychosis and high-risk of psychosis: A systematic review and meta-analysis.
      ), this suggests that impaired frontal neuronal function is associated with elevated striatal dopamine release. Consistent with this, altered prefrontal activation during cognitive tasks testing verbal fluency and working memory has also been shown to directly relate to striatal dopamine function in schizophrenia and people at risk of psychosis (
      • Fusar-Poli P.
      • Howes O.D.
      • Allen P.
      • Broome M.
      • Valli I.
      • Asselin M.C.
      • et al.
      Abnormal prefrontal activation directly related to pre-synaptic striatal dopamine dysfunction in people at clinical high risk for psychosis.
      ,
      • Meyer-Lindenberg A.
      • Kohn P.D.
      • Kolachana B.
      • Kippenhan S.
      • McInerney-Leo A.
      • Nussbaum R.
      • et al.
      Midbrain dopamine and prefrontal function in humans: Interaction and modulation by COMT genotype.
      ). Glutamate concentration in the anterior cingulate cortex has also been shown to correlate with striatal dopamine synthesis capacity in first-episode psychosis patients but not in control subjects (
      • Jauhar S.
      • McCutcheon R.
      • Borgan F.
      • Veronese M.
      • Nour M.
      • Pepper F.
      • et al.
      The relationship between cortical glutamate and striatal dopamine in first-episode psychosis: A cross-sectional multimodal PET and magnetic resonance spectroscopy imaging study.
      ). Thus, overall, preclinical studies show that the frontal cortex regulates striatal dopamine function, and healthy volunteer challenge and patient studies show that frontal function is linked to striatal dopamine measures.

      Effects of Stress on E/I Balance and Synaptic Density

      Rodent studies show that a range of stressors affect frontal E/I balance. Prenatal stress exposure (
      • Marchisella F.
      • Creutzberg K.C.
      • Begni V.
      • Sanson A.
      • Wearick-Silva L.E.
      • Tractenberg S.G.
      • et al.
      Exposure to prenatal stress is associated with an excitatory/inhibitory imbalance in rat prefrontal cortex and amygdala and an increased risk for emotional dysregulation.
      ), social instability stress (
      • Wang H.L.
      • Sun Y.X.
      • Liu X.
      • Wang H.
      • Ma Y.N.
      • Su Y.A.
      • et al.
      Adolescent stress increases depression-like behaviors and alters the excitatory-inhibitory balance in aged mice.
      ), and stress during adolescence are all associated with altered excitability of the PFC and changes in E/I molecular markers (
      • Albrecht A.
      • Ivens S.
      • Papageorgiou I.E.
      • Çalışkan G.
      • Saiepour N.
      • Brück W.
      • et al.
      Shifts in excitatory/inhibitory balance by juvenile stress: A role for neuron-astrocyte interaction in the dentate gyrus.
      ). Acute stress has also been shown to decrease synchronous activity of both excitatory and inhibitory neurons (
      • Han K.
      • Lee M.
      • Lim H.K.
      • Jang M.W.
      • Kwon J.
      • Lee C.J.
      • et al.
      Excitation-inhibition imbalance leads to alteration of neuronal coherence and neurovascular coupling under acute stress.
      ). Moreover, cortical E/I imbalance caused by stress in the adolescent period persists into adulthood along with impaired GABA and glutamate uptake into neurons (
      • Albrecht A.
      • Ivens S.
      • Papageorgiou I.E.
      • Çalışkan G.
      • Saiepour N.
      • Brück W.
      • et al.
      Shifts in excitatory/inhibitory balance by juvenile stress: A role for neuron-astrocyte interaction in the dentate gyrus.
      ).
      Prenatal and adolescent stress exposure also result in PFC and hippocampal synaptic loss mediated by microglia (
      • Hayashi A.
      • Nagaoka M.
      • Yamada K.
      • Ichitani Y.
      • Miake Y.
      • Okado N.
      Maternal stress induces synaptic loss and developmental disabilities of offspring.
      ,
      • Leussis M.P.
      • Lawson K.
      • Stone K.
      • Andersen S.L.
      The enduring effects of an adolescent social stressor on synaptic density, part II: Poststress reversal of synaptic loss in the cortex by adinazolam and MK-801.
      ,
      • Bueno-Fernandez C.
      • Perez-Rando M.
      • Alcaide J.
      • Coviello S.
      • Sandi C.
      • Castillo-Gómez E.
      • Nacher J.
      Long term effects of peripubertal stress on excitatory and inhibitory circuits in the prefrontal cortex of male and female mice.
      ,
      • Ota K.T.
      • Liu R.J.
      • Voleti B.
      • Maldonado-Aviles J.G.
      • Duric V.
      • Iwata M.
      • et al.
      REDD1 is essential for stress-induced synaptic loss and depressive behavior.
      ,
      • Milior G.
      • Lecours C.
      • Samson L.
      • Bisht K.
      • Poggini S.
      • Pagani F.
      • et al.
      Fractalkine receptor deficiency impairs microglial and neuronal responsiveness to chronic stress.
      ,
      • Wohleb E.S.
      • Terwilliger R.
      • Duman C.H.
      • Duman R.S.
      Stress-induced neuronal colony stimulating factor 1 provokes microglia-mediated neuronal remodeling and depressive-like behavior.
      ,
      • Musazzi L.
      • Treccani G.
      • Popoli M.
      Functional and structural remodeling of glutamate synapses in prefrontal and frontal cortex induced by behavioral stress.
      ). Studies investigating mechanisms of stress-related neuronal remodeling suggest that it occurs at least in part through complement-dependent synaptic elimination. Chronic stress upregulates complement C3, a molecular tag that labels synapses for deletion by microglia (
      • Bollinger J.L.
      • Horchar M.J.
      • Wohleb E.S.
      Diazepam limits microglia-mediated neuronal remodeling in the prefrontal cortex and associated behavioral consequences following chronic unpredictable stress.
      ,
      • Crider A.
      • Feng T.
      • Pandya C.D.
      • Davis T.
      • Nair A.
      • Ahmed A.O.
      • et al.
      Complement component 3a receptor deficiency attenuates chronic stress-induced monocyte infiltration and depressive-like behavior.
      ). Viral upregulation of C3 similarly enhances synaptic pruning, while C3 knockouts have a reduced stress response to social withdrawal (
      • Milior G.
      • Lecours C.
      • Samson L.
      • Bisht K.
      • Poggini S.
      • Pagani F.
      • et al.
      Fractalkine receptor deficiency impairs microglial and neuronal responsiveness to chronic stress.
      ,
      • Wohleb E.S.
      • Terwilliger R.
      • Duman C.H.
      • Duman R.S.
      Stress-induced neuronal colony stimulating factor 1 provokes microglia-mediated neuronal remodeling and depressive-like behavior.
      ). There is also evidence for altered markers of microglial activity in schizophrenia (
      • Marques T.R.
      • Ashok A.H.
      • Pillinger T.
      • Veronese M.
      • Turkheimer F.E.
      • Dazzan P.
      • et al.
      Neuroinflammation in schizophrenia: Meta-analysis of in vivo microglial imaging studies.
      ). Together, these findings suggest that microglia may mediate aberrant synaptic pruning that leads to E/I imbalance.
      Numerous rodent studies show that effects on E/I balance and enhanced microglial pruning and resultant synaptic loss are more marked in males than females (
      • Bale T.L.
      • Epperson C.N.
      Sex differences and stress across the lifespan.
      ,
      • Hodes G.E.
      • Pfau M.L.
      • Purushothaman I.
      • Ahn H.F.
      • Golden S.A.
      • Christoffel D.J.
      • et al.
      Sex differences in nucleus accumbens transcriptome profiles associated with susceptibility versus resilience to subchronic variable stress.
      ). For example, PFC E/I imbalance due to prenatal stress was shown in male but not female rodents (
      • Marchisella F.
      • Creutzberg K.C.
      • Begni V.
      • Sanson A.
      • Wearick-Silva L.E.
      • Tractenberg S.G.
      • et al.
      Exposure to prenatal stress is associated with an excitatory/inhibitory imbalance in rat prefrontal cortex and amygdala and an increased risk for emotional dysregulation.
      ). Chronic unpredictable stress causing synapse elimination by glia was also shown in males only (
      • Bueno-Fernandez C.
      • Perez-Rando M.
      • Alcaide J.
      • Coviello S.
      • Sandi C.
      • Castillo-Gómez E.
      • Nacher J.
      Long term effects of peripubertal stress on excitatory and inhibitory circuits in the prefrontal cortex of male and female mice.
      ,
      • Ota K.T.
      • Liu R.J.
      • Voleti B.
      • Maldonado-Aviles J.G.
      • Duric V.
      • Iwata M.
      • et al.
      REDD1 is essential for stress-induced synaptic loss and depressive behavior.
      ). Thus, greater vulnerability to the effects of stress on synaptic elimination could account for findings that schizophrenia shows an earlier onset in men than in women (
      • McCutcheon R.A.
      • Reis Marques T.
      • Howes O.D.
      Schizophrenia—An overview.
      ).

      An Integrated Hypothesis

      The evidence reviewed above suggests that there may be a failure to form synapses and/or greater elimination of them later in neurodevelopment in people who go on to develop schizophrenia, an effect which is at least partly mediated by genetic risk variants that dysregulate pruning of synapses by microglia. Moreover, genetic vulnerability for schizophrenia affects multiple genes involved in excitatory and inhibitory signaling. This could make circuits particularly vulnerable to tip into E/I imbalance during adolescence and early adulthood, when there is significant refinement of synapses during normal neurodevelopment.
      Environmental risk factors for schizophrenia, such as psychosocial stressors, could then act on this vulnerable system. As discussed earlier, stress leads to increased glutamatergic synaptic elimination in frontal cortical regions. We propose that this leads to preferential loss of local excitatory synapses that provide feedback regulation of pyramidal neurons to tip vulnerable cortical circuits into E/I imbalance (Figure 3). This is anticipated to lead to increased noise in cortical circuits, impairing cortical function and leading to the cognitive and negative symptoms of the disorder. We propose that this also disinhibits excitatory projections that regulate mesostriatal dopamine neurons, resulting in dopamine dysregulation and psychotic symptoms through disrupting prediction error signaling [for a review see (
      • Howes O.D.
      • Hird E.J.
      • Adams R.A.
      • Corlett P.R.
      • McGuire P.
      Aberrant salience, information processing, and dopaminergic signaling in people at clinical high risk for psychosis.
      )]; this process is outlined in Figures 4 and 5. The late maturation of the frontal cortex, and findings that stress leads to synaptic elimination there, make it particularly vulnerable to tip into E/I imbalance, although other regions may also be affected.
      Figure thumbnail gr3
      Figure 3Aberrant E/I balance in the frontal cortex of patients with schizophrenia. Lower levels of excitatory synaptic inputs onto inhibitory interneurons (shown in green) are proposed to result in increased activity of pyramidal neurons (shown in orange, arrows indicate activity). E/I, excitation-inhibition.
      Figure thumbnail gr4
      Figure 4Projections from the frontal cortex to the striatum and midbrain origin of dopamine neurons. Frontal E/I imbalance could lead to dopamine dysfunction in schizophrenia. Orange arrows indicate cortical glutamatergic projections, blue arrow indicates dopaminergic projections from substantia nigra/ventral tegmental area to caudate. Cognitive symptoms include impairments in working memory, attention, and executive function. E/I, excitation-inhibition.
      Figure thumbnail gr5
      Figure 5Integrative hypothesis showing how E/I imbalance could lead to onset of cognitive symptoms (e.g., impairments in working memory, processing speed, and executive function) and negative symptoms (e.g., amotivation and flattening of emotions) of schizophrenia as well as to striatal dopaminergic dysfunction, which underlies psychotic symptoms. E/I, excitation-inhibition.
      The timing of these processes fits with the time course for the development of symptoms, which typically begin with cognitive impairments, and then the development of negative symptoms followed by psychotic symptoms (
      • McCutcheon R.A.
      • Krystal J.H.
      • Howes O.D.
      Dopamine and glutamate in schizophrenia: Biology, symptoms and treatment.
      ).

      Outstanding Issues

      We use the term E/I imbalance to highlight that it remains to be established whether it is excitatory or inhibitory changes that are causal in schizophrenia and because a change in excitation could lead to knock-on changes in inhibition and vice versa, resulting in similar disruption of cortical circuits. Thus, key questions are the precise localization of E/I imbalance within cortical circuitry, the direction of the shift in E/I at different developmental time points, and whether aberrant pruning affects specific circuits or is a global process. We have proposed that there is preferential loss of local excitatory synapses that provide feedback regulation of pyramidal neurons. However, while there is some supporting evidence for this from in vivo and in vitro studies (
      • Chung D.W.
      • Wills Z.P.
      • Fish K.N.
      • Lewis D.A.
      Developmental pruning of excitatory synaptic inputs to parvalbumin interneurons in monkey prefrontal cortex.
      ,
      • Chung D.W.
      • Chung Y.
      • Bazmi H.H.
      • Lewis D.A.
      Altered ErbB4 splicing and cortical parvalbumin interneuron dysfunction in schizophrenia and mood disorders.
      ), further work is required to replicate these findings and investigate whether other glutamatergic synapses may also be lost. Given that markers of frontal E/I balance in schizophrenia differ depending on the anatomical resolution studied (
      • Dienel S.J.
      • Enwright 3rd, J.F.
      • Hoftman G.D.
      • Lewis D.A.
      Markers of glutamate and GABA neurotransmission in the prefrontal cortex of schizophrenia subjects: Disease effects differ across anatomical levels of resolution.
      ), it is important to carry out layer- and cell type–specific studies to address these issues as well as preclinical studies to determine whether loss of excitatory input onto GABAergic interneurons leads to phenotypes associated with schizophrenia. It is also unclear how aberrant pruning affects inhibitory synapses and whether changes to inhibitory signaling contribute to adaptive compensatory change or toward pathology. In addition, there is some evidence that areas other than the PFC, such as the hippocampus, are vulnerable to synaptic loss, and further work is required to map how other regions may contribute to disturbances discussed in this review.
      Furthermore, while we have highlighted the potential role of C4A in schizophrenia, multiple interacting proteins in the complement systems as well as other factors that modulate complement and microglial activity are involved in synaptic pruning (
      • Gomez-Arboledas A.
      • Acharya M.M.
      • Tenner A.J.
      The role of complement in synaptic pruning and neurodegeneration.
      ). It remains to be determined whether and how these contribute to a vulnerability to aberrant synaptic pruning in schizophrenia.
      We have also proposed that there is impaired synaptic formation early in neurodevelopment in schizophrenia. While there is less evidence for this, iPSC studies modeling circuit formation may be useful to better model this developmental stage in schizophrenia. It should also be recognized that synaptic plasticity, and not just absolute synaptic density, is important to cognitive development (
      • Shaw P.
      • Greenstein D.
      • Lerch J.
      • Clasen L.
      • Lenroot R.
      • Gogtay N.
      • et al.
      Intellectual ability and cortical development in children and adolescents.
      ).
      One final issue is that while, as we have highlighted, there are data showing that frontal and striatal dopamine function are related in schizophrenia, the causal relationship we propose has not been directly tested in patients. This requires longitudinal studies to investigate whether aberrant pruning and E/I imbalance lead to striatal hyperactivity via PFC dysfunction and whether overpruning in schizophrenia may continue into adulthood.
      Finally, stress is a risk factor for many other psychiatric disorders, but why does it lead to schizophrenia in some people and other presentations in others? The answer likely lies in the individual’s other vulnerability factors, particularly genetic variants, which influence the circuits that are vulnerable to the effects of stress on synaptic pruning. Studies investigating the interactions between these factors and the effects of stress would help address this issue. It should also be recognized that, while the genetic variants implicating synaptic alterations in schizophrenia that we have discussed are significant at the genome-wide level, it remains unclear how prevalent they are across cases. Similarly, some other variants associated with schizophrenia do not currently implicate synaptic alterations, and some patients do not show the dopaminergic alterations seen in the majority (
      • Jauhar S.
      • Veronese M.
      • Nour M.M.
      • Rogdaki M.
      • Hathway P.
      • Turkheimer F.E.
      • et al.
      Determinants of treatment response in first-episode psychosis: An 18 F-DOPA PET study.
      ,
      • Veronese M.
      • Santangelo B.
      • Jauhar S.
      • D’Ambrosio E.
      • Demjaha A.
      • Salimbeni H.
      • et al.
      A potential biomarker for treatment stratification in psychosis: Evaluation of an [18 F] FDOPA PET imaging approach.
      ). Thus, other mechanisms may underlie symptoms in these patients, consistent with the idea that there are neurobiological subtypes in schizophrenia (
      • Howes O.D.
      • Kapur S.
      A neurobiological hypothesis for the classification of schizophrenia: Type A (hyperdopaminergic) and type B (normodopaminergic).
      ).

      Implications for Treating Schizophrenia

      Targeting E/I imbalance may be a novel approach to treating cognitive and negative symptoms of schizophrenia. There are a number of potentially procognitive compounds in development that could do this such as modulators of inhibitory interneurons (
      • Kaar S.J.
      • Natesan S.
      • McCutcheon R.
      • Howes O.D.
      Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology.
      ), SV2A (Syndesi Therapeutics), and GABA and nicotinic systems (Recognify Life Sciences).
      Another novel treatment pathway is to address aberrant pruning. Minocycline is an antibiotic that inhibits microglial activation, among other actions (
      • Tikka T.
      • Fiebich B.L.
      • Goldsteins G.
      • Keinänen R.
      • Koistinaho J.
      Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia.
      ). A two-hit animal model showed that minocycline during stress exposure (the second hit) inhibited microglial activation and prevented behavioral disturbances (
      • Giovanoli S.
      • Engler H.
      • Engler A.
      • Richetto J.
      • Feldon J.
      • Riva M.A.
      • et al.
      Preventive effects of minocycline in a neurodevelopmental two-hit model with relevance to schizophrenia.
      ). A study also showed that minocycline or doxycycline exposure for at least 90 days during adolescence was associated with a lower risk for psychosis (
      • Sellgren C.M.
      • Gracias J.
      • Watmuff B.
      • Biag J.D.
      • Thanos J.M.
      • Whittredge P.B.
      • et al.
      Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning.
      ). In contrast, trials of minocycline as an adjunctive treatment in schizophrenia have been mixed (
      • Chaudhry I.B.
      • Hallak J.
      • Husain N.
      • Minhas F.
      • Stirling J.
      • Richardson P.
      • et al.
      Minocycline benefits negative symptoms in early schizophrenia: A randomised double-blind placebo-controlled clinical trial in patients on standard treatment.
      ,
      • Solmi M.
      • Veronese N.
      • Thapa N.
      • Facchini S.
      • Stubbs B.
      • Fornaro M.
      • et al.
      Systematic review and meta-analysis of the efficacy and safety of minocycline in schizophrenia.
      ), suggesting that more specific treatments may be needed.

      Conclusions

      Schizophrenia is associated with a genetic predisposition affecting proteins involved in excitatory and inhibitory signaling and with postmortem and in vivo evidence for this. Evidence of lower synaptic density and progressive gray matter changes in the disorder suggest that there is disruption in synaptic formation and elimination, particularly in the frontal cortex, although the timing of this remains to be established. We propose that overpruning of cortical glutamatergic synapses during adolescence may tip vulnerable circuits into E/I imbalance, leading to the onset of cognitive and negative symptoms of schizophrenia beginning in the prodrome. Evidence linking frontal cortical abnormalities to disinhibition of mesolimbic striatal dopamine signaling suggests that this process may underlie the eventual onset of psychotic symptoms. In vivo evidence shows that stress during adolescence results in increased synaptic elimination and E/I imbalance. This may be the mechanism through which environmental risk factors predispose someone to develop schizophrenia. This model ties the neurodevelopmental and dopamine hypotheses of schizophrenia into a single pathoetiological hypothesis and identifies preventive therapies targeting pruning and those correcting frontal E/I imbalance as important avenues for future research.

      Acknowledgments and Disclosures

      We thank Dr. Robert McCutcheon for his critical reading of the manuscript.
      ODH is a part-time employee of H Lundbeck A/S. He has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organized by Angellini, Autifony, Biogen , Boehringer Ingelheim , Eli Lilly , Heptares, Global Medical Education, Invicro, Jansenn, Lundbeck , Neurocrine, Otsuka, Sunovion , Recordati, Roche , and Viatris/ Mylan . Neither ODH nor his family have holdings/a financial stake in any pharmaceutical company. ODH has a patent for the use of dopaminergic imaging. ES reports no biomedical financial interests or potential conflicts of interest. The views expressed are those of the authors and not necessarily those of H Lundbeck A/s, the NHS/NIHR, or the Department of Health.

      Supplementary Material

      References

        • McCutcheon R.A.
        • Reis Marques T.
        • Howes O.D.
        Schizophrenia—An overview.
        JAMA Psychiatry. 2020; 77: 201-210
        • Howes O.D.
        • Kapur S.
        The dopamine hypothesis of schizophrenia: Version III–the final common pathway.
        Schizophr Bull. 2009; 35: 549-562
        • Murray R.M.
        • Lewis S.W.
        Is schizophrenia a neurodevelopmental disorder?.
        Br Med J (Clin Res Ed). 1987; 295: 681-682
        • Marenco S.
        • Weinberger D.R.
        The neurodevelopmental hypothesis of schizophrenia: Following a trail of evidence from cradle to grave.
        Dev Psychopathol. 2000; 12: 501-527
        • Murray R.M.
        • Bhavsar V.
        • Tripoli G.
        • Howes O.
        30 years on: How the neurodevelopmental hypothesis of schizophrenia morphed into the developmental risk factor model of psychosis.
        Schizophr Bull. 2017; 43: 1190-1196
        • Grace A.A.
        Dysregulation of the dopamine system in the pathophysiology of schizophrenia and depression.
        Nat Rev Neurosci. 2016; 17: 524-532
        • Insel T.R.
        Rethinking schizophrenia.
        Nature. 2010; 468: 187-193
        • Lewis D.A.
        • Hashimoto T.
        • Volk D.W.
        Cortical inhibitory neurons and schizophrenia.
        Nat Rev Neurosci. 2005; 6: 312-324
        • Drzewiecki C.M.
        • Willing J.
        • Juraska J.M.
        Synaptic number changes in the medial prefrontal cortex across adolescence in male and female rats: A role for pubertal onset.
        Synapse. 2016; 70: 361-368
        • Crain B.
        • Cotman C.
        • Taylor D.
        • Lynch G.
        A quantitative electron microscopic study of synaptogenesis in the dentate gyrus of the rat.
        Brain Res. 1973; 63: 195-204
        • Zecevic N.
        • Bourgeois J.P.
        • Rakic P.
        Changes in synaptic density in motor cortex of rhesus monkey during fetal and postnatal life.
        Brain Res Dev Brain Res. 1989; 50: 11-32
        • Rakic P.
        • Bourgeois J.P.
        • Eckenhoff M.F.
        • Zecevic N.
        • Goldman-Rakic P.S.
        Concurrent overproduction of synapses in diverse regions of the primate cerebral cortex.
        Science. 1986; 232: 232-235
        • Bourgeois J.P.
        • Rakic P.
        Changes of synaptic density in the primary visual cortex of the macaque monkey from fetal to adult stage.
        J Neurosci. 1993; 13: 2801-2820
        • Pinto J.G.
        • Jones D.G.
        • Murphy K.M.
        Comparing development of synaptic proteins in rat visual, somatosensory, and frontal cortex.
        Front Neural Circuits. 2013; 7: 97
        • Huttenlocher P.R.
        Synaptic density in human frontal cortex – developmental changes and effects of aging.
        Brain Res. 1979; 163: 195-205
        • Petanjek Z.
        • Judaš M.
        • Šimic G.
        • Rasin M.R.
        • Uylings H.B.
        • Rakic P.
        • Kostovic I.
        Extraordinary neoteny of synaptic spines in the human prefrontal cortex.
        Proc Natl Acad Sci U S A. 2011; 108: 13281-13286
        • Huttenlocher P.R.
        • Dabholkar A.S.
        Regional differences in synaptogenesis in human cerebral cortex.
        J Comp Neurol. 1997; 387: 167-178
        • Pinto J.G.
        • Jones D.G.
        • Williams C.K.
        • Murphy K.M.
        Characterizing synaptic protein development in human visual cortex enables alignment of synaptic age with rat visual cortex.
        Front Neural Circuits. 2015; 9: 3
        • Shaw P.
        • Kabani N.J.
        • Lerch J.P.
        • Eckstrand K.
        • Lenroot R.
        • Gogtay N.
        • et al.
        Neurodevelopmental trajectories of the human cerebral cortex.
        J Neurosci. 2008; 28: 3586-3594
        • Lenroot R.K.
        • Giedd J.N.
        Brain development in children and adolescents: Insights from anatomical magnetic resonance imaging.
        Neurosci Biobehav Rev. 2006; 30: 718-729
        • Giorgio A.
        • Santelli L.
        • Tomassini V.
        • Bosnell R.
        • Smith S.
        • De Stefano N.
        • Johansen-Berg H.
        Age-related changes in grey and white matter structure throughout adulthood.
        Neuroimage. 2010; 51: 943-951
        • Gogtay N.
        • Giedd J.N.
        • Lusk L.
        • Hayashi K.M.
        • Greenstein D.
        • Vaituzis A.C.
        • et al.
        Dynamic mapping of human cortical development during childhood through early adulthood.
        Proc Natl Acad Sci U S A. 2004; 101: 8174-8179
        • Giedd J.N.
        • Blumenthal J.
        • Jeffries N.O.
        • Castellanos F.X.
        • Liu H.
        • Zijdenbos A.
        • et al.
        Brain development during childhood and adolescence: A longitudinal MRI study.
        Nat Neurosci. 1999; 2: 861-863
        • White T.
        • Su S.
        • Schmidt M.
        • Kao C.Y.
        • Sapiro G.
        The development of gyrification in childhood and adolescence.
        Brain Cogn. 2010; 72: 36-45
        • Zakharova N.V.
        • Mamedova G.S.
        • Bravve L.V.
        • Kaydan M.A.
        • Syunyakov T.S.
        • Kostyuk G.P.
        • Ushakov V.L.
        Brain gyrification index in schizophrenia (review, systematic review and meta-analysis).
        Procedia Comput Sci. 2021; 190: 825-837
        • Yücel M.
        • Stuart G.W.
        • Maruff P.
        • Wood S.J.
        • Savage G.R.
        • Smith D.J.
        • et al.
        Paracingulate morphologic differences in males with established schizophrenia: A magnetic resonance imaging morphometric study.
        Biol Psychiatry. 2002; 52: 15-23
        • Narr K.L.
        • Thompson P.M.
        • Sharma T.
        • Moussai J.
        • Zoumalan C.
        • Rayman J.
        • Toga A.
        Three-dimensional mapping of gyral shape and cortical surface asymmetries in schizophrenia: Gender effects.
        Am J Psychiatry. 2001; 158: 244-255
        • Vogeley K.
        • Schneider-Axmann T.
        • Pfeiffer U.
        • Tepest R.
        • Bayer T.A.
        • Bogerts B.
        • et al.
        Disturbed gyrification of the prefrontal region in male schizophrenic patients: A morphometric postmortem study.
        Am J Psychiatry. 2000; 157: 34-39
        • Brugger S.P.
        • Howes O.D.
        Heterogeneity and homogeneity of regional brain structure in schizophrenia: A meta-analysis.
        JAMA Psychiatry. 2017; 74: 1104-1111
        • Schnack H.G.
        • Van Haren N.E.
        • Nieuwenhuis M.
        • Hulshoff Pol H.E.
        • Cahn W.
        • Kahn R.S.
        Accelerated brain aging in schizophrenia: A longitudinal pattern recognition study.
        Am J Psychiatry. 2016; 173: 607-616
        • Vita A.
        • De Peri L.
        • Deste G.
        • Sacchetti E.
        Progressive loss of cortical gray matter in schizophrenia: A meta-analysis and meta-regression of longitudinal MRI studies [published correction appears in Transl Psychiatry. 2013;3:e275].
        Transl Psychiatry. 2012; 2: e190
        • Cropley V.L.
        • Klauser P.
        • Lenroot R.K.
        • Bruggemann J.
        • Sundram S.
        • Bousman C.
        • et al.
        Accelerated gray and white matter deterioration with age in schizophrenia.
        Am J Psychiatry. 2017; 174: 286-295
        • Selemon L.D.
        • Goldman-Rakic P.S.
        The reduced neuropil hypothesis: A circuit based model of schizophrenia.
        Biol Psychiatry. 1999; 45: 17-25
        • Haijma S.V.
        • Van Haren N.
        • Cahn W.
        • Koolschijn P.C.
        • Hulshoff Pol H.E.
        • Kahn R.S.
        Brain volumes in schizophrenia: A meta-analysis in over 18 000 subjects.
        Schizophr Bull. 2013; 39: 1129-1138
        • Olabi B.
        • Ellison-Wright I.
        • McIntosh A.M.
        • Wood S.J.
        • Bullmore E.
        • Lawrie S.M.
        Are there progressive brain changes in schizophrenia? A meta-analysis of structural magnetic resonance imaging studies.
        Biol Psychiatry. 2011; 70: 88-96
        • Douaud G.
        • Mackay C.
        • Andersson J.
        • James S.
        • Quested D.
        • Ray M.K.
        • et al.
        Schizophrenia delays and alters maturation of the brain in adolescence.
        Brain. 2009; 132: 2437-2448
        • Brans R.G.
        • van Haren N.E.
        • van Baal G.C.M.
        • Schnack H.G.
        • Kahn R.S.
        • Hulshoff Pol H.E.H.
        Heritability of changes in brain volume over time in twin pairs discordant for schizophrenia.
        Arch Gen Psychiatry. 2008; 65: 1259-1268
        • Ho B.C.
        • Alicata D.
        • Ward J.
        • Moser D.J.
        • O’Leary D.S.
        • Arndt S.
        • Andreasen N.C.
        Untreated initial psychosis: Relation to cognitive deficits and brain morphology in first-episode schizophrenia.
        Am J Psychiatry. 2003; 160: 142-148
        • Dietsche B.
        • Kircher T.
        • Falkenberg I.
        Structural brain changes in schizophrenia at different stages of the illness: A selective review of longitudinal magnetic resonance imaging studies.
        Aust N Z J Psychiatry. 2017; 51: 500-508
        • Andreasen N.C.
        • Nopoulos P.
        • Magnotta V.
        • Pierson R.
        • Ziebell S.
        • Ho B.C.
        Progressive brain change in schizophrenia: A prospective longitudinal study of first-episode schizophrenia.
        Biol Psychiatry. 2011; 70: 672-679
        • Ho B.C.
        • Andreasen N.C.
        • Ziebell S.
        • Pierson R.
        • Magnotta V.
        Long-term antipsychotic treatment and brain volumes: A longitudinal study of first-episode schizophrenia.
        Arch Gen Psychiatry. 2011; 68: 128-137
        • Osimo E.F.
        • Beck K.
        • Reis Marques T.R.
        • Howes O.D.
        Synaptic loss in schizophrenia: A meta-analysis and systematic review of synaptic protein and mRNA measures.
        Mol Psychiatry. 2019; 24: 549-561
        • Berdenis van Berlekom A.
        • Muflihah C.H.
        • Snijders G.J.L.J.
        • MacGillavry H.D.
        • Middeldorp J.
        • Hol E.M.
        • et al.
        Synapse pathology in schizophrenia: A meta-analysis of postsynaptic elements in postmortem brain studies.
        Schizophr Bull. 2020; 46: 374-386
        • Lynch B.A.
        • Lambeng N.
        • Nocka K.
        • Kensel-Hammes P.
        • Bajjalieh S.M.
        • Matagne A.
        • Fuks B.
        The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam.
        Proc Natl Acad Sci U S A. 2004; 101: 9861-9866
        • Finnema S.J.
        • Nabulsi N.B.
        • Mercier J.
        • Lin S.F.
        • Chen M.K.
        • Matuskey D.
        • et al.
        Kinetic evaluation and test–retest reproducibility of [11C] UCB-J, a novel radioligand for positron emission tomography imaging of synaptic vesicle glycoprotein 2A in humans.
        J Cereb Blood Flow Metab. 2018; 38: 2041-2052
        • Onwordi E.C.
        • Halff E.F.
        • Whitehurst T.
        • Mansur A.
        • Cotel M.C.
        • Wells L.
        • et al.
        Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats.
        Nat Commun. 2020; 11: 246
        • Radhakrishnan R.
        • Skosnik P.D.
        • Ranganathan M.
        • Naganawa M.
        • Toyonaga T.
        • Finnema S.
        • et al.
        In vivo evidence of lower synaptic vesicle density in schizophrenia.
        Mol Psychiatry. 2021; 26: 7690-7698
        • Onwordi E.C.
        • Whitehurst T.
        • Mansur A.
        • Statton B.
        • Berry A.
        • Quinlan M.
        • et al.
        The relationship between synaptic density marker SV2A, glutamate and N-acetyl aspartate levels in healthy volunteers and schizophrenia: A multimodal PET and magnetic resonance spectroscopy brain imaging study.
        Transl Psychiatry. 2021; 11: 393
        • Sellgren C.M.
        • Gracias J.
        • Watmuff B.
        • Biag J.D.
        • Thanos J.M.
        • Whittredge P.B.
        • et al.
        Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning.
        Nat Neurosci. 2019; 22: 374-385
        • Kathuria A.
        • Lopez-Lengowski K.
        • Watmuff B.
        • McPhie D.
        • Cohen B.M.
        • Karmacharya R.
        Synaptic deficits in iPSC-derived cortical interneurons in schizophrenia are mediated by NLGN2 and rescued by N-acetylcysteine.
        Transl Psychiatry. 2019; 9: 321
        • Habela C.W.
        • Song H.
        • Ming G.L.
        Modeling synaptogenesis in schizophrenia and autism using human iPSC derived neurons.
        Mol Cell Neurosci. 2016; 73: 52-62
        • Sheridan S.D.
        • Horng J.E.
        • Perlis R.H.
        Patient-derived in vitro models of microglial function and synaptic engulfment in schizophrenia.
        Biol Psychiatry. 2022; 92: 470-479
        • Froemke R.C.
        Plasticity of cortical excitatory-inhibitory balance.
        Annu Rev Neurosci. 2015; 38: 195-219
        • Dorrn A.L.
        • Yuan K.
        • Barker A.J.
        • Schreiner C.E.
        • Froemke R.C.
        Developmental sensory experience balances cortical excitation and inhibition.
        Nature. 2010; 465: 932-936
        • Hensch T.K.
        • Fagiolini M.
        Excitatory–inhibitory balance and critical period plasticity in developing visual cortex.
        Prog Brain Res. 2005; 147: 115-124
        • Hensch T.K.
        Critical period regulation.
        Annu Rev Neurosci. 2004; 27: 549-579
        • Paolicelli R.C.
        • Bolasco G.
        • Pagani F.
        • Maggi L.
        • Scianni M.
        • Panzanelli P.
        • et al.
        Synaptic pruning by microglia is necessary for normal brain development.
        Science. 2011; 333: 1456-1458
        • Stephan A.H.
        • Barres B.A.
        • Stevens B.
        The complement system: An unexpected role in synaptic pruning during development and disease.
        Annu Rev Neurosci. 2012; 35: 369-389
        • Chu Y.
        • Jin X.
        • Parada I.
        • Pesic A.
        • Stevens B.
        • Barres B.
        • Prince D.A.
        Enhanced synaptic connectivity and epilepsy in C1q knockout mice.
        Proc Natl Acad Sci U S A. 2010; 107: 7975-7980
        • Yilmaz M.
        • Yalcin E.
        • Presumey J.
        • Aw E.
        • Ma M.
        • Whelan C.W.
        • et al.
        Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice.
        Nat Neurosci. 2021; 24: 214-224
        • Sekar A.
        • Bialas A.R.
        • De Rivera H.
        • Davis A.
        • Hammond T.R.
        • Kamitaki N.
        • et al.
        Schizophrenia risk from complex variation of complement component 4.
        Nature. 2016; 530: 177-183
        • Ikeda M.
        • Takahashi A.
        • Kamatani Y.
        • Momozawa Y.
        • Saito T.
        • Kondo K.
        • et al.
        Genome-wide association study detected novel susceptibility genes for schizophrenia and shared trans-populations/diseases genetic effect.
        Schizophr Bull. 2019; 45: 824-834
        • Paul A.
        • Nawalpuri B.
        • Shah D.
        • Sateesh S.
        • Muddashetty R.S.
        • Clement J.P.
        Differential regulation of Syngap1 translation by FMRP modulates eEF2 mediated response on NMDAR activity.
        Front Mol Neurosci. 2019; 12: 97
        • Yu H.
        • Yan H.
        • Li J.
        • Li Z.
        • Zhang X.
        • Ma Y.
        • et al.
        Common variants on 2p16.1, 6p22.1 and 10q24. 32 are associated with schizophrenia in Han Chinese population.
        Mol Psychiatry. 2017; 22: 954-960
        • Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium
        Genome-wide association study identifies five new schizophrenia loci.
        Nat Genet. 2011; 43: 969-976
        • Bergen S.E.
        • O’dushlaine C.T.
        • Ripke S.
        • Lee P.H.
        • Ruderfer D.M.
        • Akterin S.
        • et al.
        Genome-wide association study in a Swedish population yields support for greater CNV and MHC involvement in schizophrenia compared with bipolar disorder.
        Mol Psychiatry. 2012; 17: 880-886
        • Yang Y.
        • He M.
        • Tian X.
        • Guo Y.
        • Liu F.
        • Li Y.
        • et al.
        Transgenic overexpression of furin increases epileptic susceptibility.
        Cell Death Dis. 2018; 9: 1058
        • Riazanski V.
        • Deriy L.V.
        • Shevchenko P.D.
        • Le B.
        • Gomez E.A.
        • Nelson D.J.
        Presynaptic CLC-3 determines quantal size of inhibitory transmission in the hippocampus.
        Nat Neurosci. 2011; 14: 487-494
        • Barešić A.
        • Nash A.J.
        • Dahoun T.
        • Howes O.
        • Lenhard B.
        Understanding the genetics of neuropsychiatric disorders: The potential role of genomic regulatory blocks.
        Mol Psychiatry. 2020; 25: 6-18
        • Amin H.
        • Marinaro F.
        • Tonelli D.D.P.
        • Berdondini L.
        Developmental excitatory-to-inhibitory GABA-polarity switch is disrupted in 22q11. 2 deletion syndrome: A potential target for clinical therapeutics.
        Sci Rep. 2017; 7: 15752
        • Uhlhaas P.J.
        • Singer W.
        Oscillations and neuronal dynamics in schizophrenia: The search for basic symptoms and translational opportunities.
        Biol Psychiatry. 2015; 77: 1001-1009
        • Bianciardi B.
        • Uhlhaas P.J.
        Do NMDA-R antagonists re-create patterns of spontaneous gamma-band activity in schizophrenia? A systematic review and perspective.
        Neurosci Biobehav Rev. 2021; 124: 308-323
        • Reilly T.J.
        • Nottage J.F.
        • Studerus E.
        • Rutigliano G.
        • Micheli A.I.D.
        • Fusar-Poli P.
        • McGuire P.
        Gamma band oscillations in the early phase of psychosis: A systematic review.
        Neurosci Biobehav Rev. 2018; 90: 381-399
        • Grent-’t-Jong T.
        • Gross J.
        • Goense J.
        • Wibral M.
        • Gajwani R.
        • Gumley A.I.
        • et al.
        Resting-state gamma-band power alterations in schizophrenia reveal E/I-balance abnormalities across illness-stages.
        eLife. 2018; 7: e37799
        • De Wilde O.M.
        • Bour L.J.
        • Dingemans P.M.
        • Koelman J.H.
        • Linszen D.H.
        A meta-analysis of P50 studies in patients with schizophrenia and relatives: Differences in methodology between research groups.
        Schizophr Res. 2007; 97: 137-151
        • Daskalakis Z.J.
        • Fitzgerald P.B.
        • Christensen B.K.
        The role of cortical inhibition in the pathophysiology and treatment of schizophrenia.
        Brain Res Rev. 2007; 56: 427-442
        • Freedman R.
        • Adams C.E.
        • Adler L.E.
        • Bickford P.C.
        • Gault J.
        • Harris J.G.
        • et al.
        Inhibitory neurophysiological deficit as a phenotype for genetic investigation of schizophrenia.
        Am J Med Genet. 2000; 97: 58-64
        • Cash R.F.
        • Noda Y.
        • Zomorrodi R.
        • Radhu N.
        • Farzan F.
        • Rajji T.K.
        • et al.
        Characterization of glutamatergic and GABAA-mediated neurotransmission in motor and dorsolateral prefrontal cortex using paired-pulse TMS–EEG.
        Neuropsychopharmacology. 2017; 42: 502-511
        • Li X.
        • Honda S.
        • Nakajima S.
        • Wada M.
        • Yoshida K.
        • Daskalakis Z.J.
        • et al.
        TMS-EEG research to elucidate the pathophysiological neural bases in patients with schizophrenia: A systematic review.
        J Pers Med. 2021; 11: 388
        • Garrido M.I.
        • Kilner J.M.
        • Stephan K.E.
        • Friston K.J.
        The mismatch negativity: A review of underlying mechanisms.
        Clin Neurophysiol. 2009; 120: 453-463
        • Umbricht D.
        • Koller R.
        • Vollenweider F.X.
        • Schmid L.
        Mismatch negativity predicts psychotic experiences induced by NMDA receptor antagonist in healthy volunteers.
        Biol Psychiatry. 2002; 51: 400-406
        • Erickson M.A.
        • Ruffle A.
        • Gold J.M.
        A meta-analysis of mismatch negativity in schizophrenia: From clinical risk to disease specificity and progression.
        Biol Psychiatry. 2016; 79: 980-987
        • Rowland L.M.
        • Summerfelt A.
        • Wijtenburg S.A.
        • Du X.
        • Chiappelli J.J.
        • Krishna N.
        • et al.
        Frontal glutamate and gamma-aminobutyric acid levels and their associations with mismatch negativity and digit sequencing task performance in schizophrenia.
        JAMA Psychiatry. 2016; 73: 166-174
        • Beck K.
        • Arumuham A.
        • Veronese M.
        • Santangelo B.
        • McGinnity C.J.
        • Dunn J.
        • et al.
        N-methyl-D-aspartate receptor availability in first-episode psychosis: A PET-MR brain imaging study.
        Transl Psychiatry. 2021; 11: 425
        • Kaar S.J.
        • Natesan S.
        • McCutcheon R.
        • Howes O.D.
        Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology.
        Neuropharmacology. 2020; 172: 107704
        • Adams R.A.
        • Pinotsis D.
        • Tsirlis K.
        • Unruh L.
        • Mahajan A.
        • Horas A.M.
        • et al.
        Computational modeling of electroencephalography and functional magnetic resonance imaging paradigms indicates a consistent loss of pyramidal cell synaptic gain in schizophrenia.
        Biol Psychiatry. 2022; 91: 202-215
        • Calvin O.L.
        • Redish A.D.
        Global disruption in excitation-inhibition balance can cause localized network dysfunction and Schizophrenia-like context-integration deficits.
        PLoS Comput Biol. 2021; 17: e1008985
        • Gonzalez-Burgos G.
        • Cho R.Y.
        • Lewis D.A.
        Alterations in cortical network oscillations and parvalbumin neurons in schizophrenia.
        Biol Psychiatry. 2015; 77: 1031-1040
        • Noda Y.
        • Barr M.S.
        • Zomorrodi R.
        • Cash R.F.H.
        • Farzan F.
        • Rajji T.K.
        • et al.
        Evaluation of short interval cortical inhibition and intracortical facilitation from the dorsolateral prefrontal cortex in patients with schizophrenia.
        Sci Rep. 2017; 7: 17106
        • Roussy M.
        • Luna R.
        • Duong L.
        • Corrigan B.
        • Gulli R.A.
        • Nogueira R.
        • et al.
        Ketamine disrupts naturalistic coding of working memory in primate lateral prefrontal cortex networks.
        Mol Psychiatry. 2021; 26: 6688-6703
        • Howes O.D.
        • Murray R.M.
        Schizophrenia: An integrated sociodevelopmental-cognitive model.
        Lancet. 2014; 383: 1677-1687
        • McCutcheon R.A.
        • Krystal J.H.
        • Howes O.D.
        Dopamine and glutamate in schizophrenia: Biology, symptoms and treatment.
        World Psychiatry. 2020; 19: 15-33
        • Carlsson A.
        Does dopamine have a role in schizophrenia?.
        Biol Psychiatry. 1978; 13: 3-21
        • Brugger S.P.
        • Angelescu I.
        • Abi-Dargham A.
        • Mizrahi R.
        • Shahrezaei V.
        • Howes O.D.
        Heterogeneity of striatal dopamine function in schizophrenia: Meta-analysis of variance.
        Biol Psychiatry. 2020; 87: 215-224
        • Howes O.D.
        • Kambeitz J.
        • Kim E.
        • Stahl D.
        • Slifstein M.
        • Abi-Dargham A.
        • Kapur S.
        The nature of dopamine dysfunction in schizophrenia and what this means for treatment.
        Arch Gen Psychiatry. 2012; 69: 776-786
        • McCutcheon R.
        • Beck K.
        • Jauhar S.
        • Howes O.D.
        Defining the locus of dopaminergic dysfunction in schizophrenia: A meta-analysis and test of the mesolimbic hypothesis.
        Schizophr Bull. 2018; 44: 1301-1311
        • Laruelle M.
        • Abi-Dargham A.
        • Van Dyck C.H.
        • Gil R.
        • D’Souza C.D.
        • Erdos J.
        • et al.
        Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects.
        Proc Natl Acad Sci U S A. 1996; 93: 9235-9240
        • Breier A.
        • Su T.P.
        • Saunders R.
        • Carson R.E.
        • Kolachana B.S.
        • De Bartolomeis A.
        • et al.
        Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: Evidence from a novel positron emission tomography method.
        Proc Natl Acad Sci U S A. 1997; 94: 2569-2574
        • Abi-Dargham A.
        • Rodenhiser J.
        • Printz D.
        • Zea-Ponce Y.
        • Gil R.
        • Kegeles L.S.
        • et al.
        Increased baseline occupancy of D2 receptors by dopamine in schizophrenia.
        Proc Natl Acad Sci U S A. 2000; 97: 8104-8109
        • Howes O.D.
        • Montgomery A.J.
        • Asselin M.C.
        • Murray R.M.
        • Valli I.
        • Tabraham P.
        • et al.
        Elevated striatal dopamine function linked to prodromal signs of schizophrenia.
        Arch Gen Psychiatry. 2009; 66: 13-20
        • Kegeles L.S.
        • Abi-Dargham A.
        • Frankle W.G.
        • Gil R.
        • Cooper T.B.
        • Slifstein M.
        • et al.
        Increased synaptic dopamine function in associative regions of the striatum in schizophrenia.
        Arch Gen Psychiatry. 2010; 67: 231-239
        • Jauhar S.
        • Nour M.M.
        • Veronese M.
        • Rogdaki M.
        • Bonoldi I.
        • Azis M.
        • et al.
        A test of the transdiagnostic dopamine hypothesis of psychosis using positron emission tomographic imaging in bipolar affective disorder and schizophrenia.
        JAMA Psychiatry. 2017; 74: 1206-1213
        • Jauhar S.
        • Veronese M.
        • Nour M.M.
        • Rogdaki M.
        • Hathway P.
        • Turkheimer F.E.
        • et al.
        Determinants of treatment response in first-episode psychosis: An 18 F-DOPA PET study.
        Mol Psychiatry. 2019; 24: 1502-1512
        • Rogdaki M.
        • Devroye C.
        • Ciampoli M.
        • Veronese M.
        • Ashok A.H.
        • McCutcheon R.A.
        • et al.
        Striatal dopaminergic alterations in individuals with copy number variants at the 22q11. 2 Genetic locus and their implications for psychosis risk: A [18F]-DOPA PET study.
        Mol Psychiatry. 2021; 1–12
        • Mizrahi R.
        • Addington J.
        • Rusjan P.M.
        • Suridjan I.
        • Ng A.
        • Boileau I.
        • et al.
        Increased stress-induced dopamine release in psychosis.
        Biol Psychiatry. 2012; 71: 561-567
        • McCutcheon R.A.
        • Merritt K.
        • Howes O.D.
        Dopamine and glutamate in individuals at high risk for psychosis: A meta-analysis of in vivo imaging findings and their variability compared to controls.
        World Psychiatry. 2021; 20: 405-416
        • Howes O.D.
        • Bonoldi I.
        • McCutcheon R.A.
        • Azis M.
        • Antoniades M.
        • Bossong M.
        • et al.
        Glutamatergic and dopaminergic function and the relationship to outcome in people at clinical high risk of psychosis: A multi-modal PET-magnetic resonance brain imaging study.
        Neuropsychopharmacology. 2020; 45: 641-648
        • Pycock C.J.
        • Carter C.J.
        • Kerwin R.W.
        Effect of 6-hydroxydopamine lesions of the medial prefrontal cortex on neurotransmitter systems in subcortical sites in the rat.
        J Neurochem. 1980; 34: 91-99
        • Pycock C.J.
        • Kerwin R.W.
        • Carter C.J.
        Effect of lesion of cortical dopamine terminals on subcortical dopamine receptors in rats.
        Nature. 1980; 286: 74-76
        • Quiroz C.
        • Orrú M.
        • Rea W.
        • Ciudad-Roberts A.
        • Yepes G.
        • Britt J.P.
        • Ferré S.
        Local control of extracellular dopamine levels in the medial nucleus accumbens by a glutamatergic projection from the infralimbic cortex.
        J Neurosci. 2016; 36: 851-859
        • Adrover M.F.
        • Shin J.H.
        • Quiroz C.
        • Ferré S.
        • Lemos J.C.
        • Alvarez V.A.
        Prefrontal cortex-driven dopamine signals in the striatum show unique spatial and pharmacological properties.
        J Neurosci. 2020; 40: 7510-7522
        • Kim I.H.
        • Rossi M.A.
        • Aryal D.K.
        • Racz B.
        • Kim N.
        • Uezu A.
        • et al.
        Spine pruning drives antipsychotic-sensitive locomotion via circuit control of striatal dopamine.
        Nat Neurosci. 2015; 18: 883-891
        • Beck K.
        • Hindley G.
        • Borgan F.
        • Ginestet C.
        • McCutcheon R.
        • Brugger S.
        • et al.
        Association of ketamine with psychiatric symptoms and implications for its therapeutic use and for understanding schizophrenia: A systematic review and meta-analysis.
        JAMA Network Open. 2020; 3: e204693
        • Kokkinou M.
        • Irvine E.E.
        • Bonsall D.R.
        • Natesan S.
        • Wells L.A.
        • Smith M.
        • et al.
        Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: A translational imaging study with ketamine.
        Mol Psychiatry. 2021; 26: 2562-2576
        • McNally J.M.
        • Aguilar D.D.
        • Katsuki F.
        • Radzik L.K.
        • Schiffino F.L.
        • Uygun D.S.
        • et al.
        Optogenetic manipulation of an ascending arousal system tunes cortical broadband gamma power and reveals functional deficits relevant to schizophrenia.
        Mol Psychiatry. 2021; 26: 3461-3475
        • Kegeles L.S.
        • Abi-Dargham A.
        • Zea-Ponce Y.
        • Rodenhiser-Hill J.
        • Mann J.J.
        • Van Heertum R.L.
        • et al.
        Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: Implications for schizophrenia.
        Biol Psychiatry. 2000; 48: 627-640
        • D’Ambrosio E.
        • Jauhar S.
        • Kim S.
        • Veronese M.
        • Rogdaki M.
        • Pepper F.
        • et al.
        The relationship between grey matter volume and striatal dopamine function in psychosis: A multimodal 18F-DOPA PET and voxel-based morphometry study.
        Mol Psychiatry. 2021; 26: 1332-1345
        • Bertolino A.
        • Breier A.
        • Callicott J.H.
        • Adler C.
        • Mattay V.S.
        • Shapiro M.
        • et al.
        The relationship between dorsolateral prefrontal neuronal N-acetylaspartate and evoked release of striatal dopamine in schizophrenia.
        Neuropsychopharmacology. 2000; 22: 125-132
        • Whitehurst T.S.
        • Osugo M.
        • Townsend L.
        • Shatalina E.
        • Vava R.
        • Onwordi E.C.
        • Howes O.
        Proton magnetic resonance spectroscopy of N-acetyl aspartate in chronic schizophrenia, first episode of psychosis and high-risk of psychosis: A systematic review and meta-analysis.
        Neurosci Biobehav Rev. 2020; 119: 255-267
        • Fusar-Poli P.
        • Howes O.D.
        • Allen P.
        • Broome M.
        • Valli I.
        • Asselin M.C.
        • et al.
        Abnormal prefrontal activation directly related to pre-synaptic striatal dopamine dysfunction in people at clinical high risk for psychosis.
        Mol Psychiatry. 2011; 16: 67-75
        • Meyer-Lindenberg A.
        • Kohn P.D.
        • Kolachana B.
        • Kippenhan S.
        • McInerney-Leo A.
        • Nussbaum R.
        • et al.
        Midbrain dopamine and prefrontal function in humans: Interaction and modulation by COMT genotype.
        Nat Neurosci. 2005; 8: 594-596
        • Jauhar S.
        • McCutcheon R.
        • Borgan F.
        • Veronese M.
        • Nour M.
        • Pepper F.
        • et al.
        The relationship between cortical glutamate and striatal dopamine in first-episode psychosis: A cross-sectional multimodal PET and magnetic resonance spectroscopy imaging study.
        Lancet Psychiatry. 2018; 5: 816-823
        • Marchisella F.
        • Creutzberg K.C.
        • Begni V.
        • Sanson A.
        • Wearick-Silva L.E.
        • Tractenberg S.G.
        • et al.
        Exposure to prenatal stress is associated with an excitatory/inhibitory imbalance in rat prefrontal cortex and amygdala and an increased risk for emotional dysregulation.
        Front Cell Dev Biol. 2021; 9: 653384
        • Wang H.L.
        • Sun Y.X.
        • Liu X.
        • Wang H.
        • Ma Y.N.
        • Su Y.A.
        • et al.
        Adolescent stress increases depression-like behaviors and alters the excitatory-inhibitory balance in aged mice.
        Chin Med J (Engl). 2019; 132: 1689-1699
        • Albrecht A.
        • Ivens S.
        • Papageorgiou I.E.
        • Çalışkan G.
        • Saiepour N.
        • Brück W.
        • et al.
        Shifts in excitatory/inhibitory balance by juvenile stress: A role for neuron-astrocyte interaction in the dentate gyrus.
        Glia. 2016; 64: 911-922
        • Han K.
        • Lee M.
        • Lim H.K.
        • Jang M.W.
        • Kwon J.
        • Lee C.J.
        • et al.
        Excitation-inhibition imbalance leads to alteration of neuronal coherence and neurovascular coupling under acute stress.
        J Neurosci. 2020; 40: 9148-9162
        • Hayashi A.
        • Nagaoka M.
        • Yamada K.
        • Ichitani Y.
        • Miake Y.
        • Okado N.
        Maternal stress induces synaptic loss and developmental disabilities of offspring.
        Int J Dev Neurosci. 1998; 16: 209-216
        • Leussis M.P.
        • Lawson K.
        • Stone K.
        • Andersen S.L.
        The enduring effects of an adolescent social stressor on synaptic density, part II: Poststress reversal of synaptic loss in the cortex by adinazolam and MK-801.
        Synapse. 2008; 62: 185-192
        • Bueno-Fernandez C.
        • Perez-Rando M.
        • Alcaide J.
        • Coviello S.
        • Sandi C.
        • Castillo-Gómez E.
        • Nacher J.
        Long term effects of peripubertal stress on excitatory and inhibitory circuits in the prefrontal cortex of male and female mice.
        Neurobiol Stress. 2021; 14: 100322
        • Ota K.T.
        • Liu R.J.
        • Voleti B.
        • Maldonado-Aviles J.G.
        • Duric V.
        • Iwata M.
        • et al.
        REDD1 is essential for stress-induced synaptic loss and depressive behavior.
        Nat Med. 2014; 20: 531-535
        • Milior G.
        • Lecours C.
        • Samson L.
        • Bisht K.
        • Poggini S.
        • Pagani F.
        • et al.
        Fractalkine receptor deficiency impairs microglial and neuronal responsiveness to chronic stress.
        Brain Behav Immun. 2016; 55: 114-125
        • Wohleb E.S.
        • Terwilliger R.
        • Duman C.H.
        • Duman R.S.
        Stress-induced neuronal colony stimulating factor 1 provokes microglia-mediated neuronal remodeling and depressive-like behavior.
        Biol Psychiatry. 2018; 83: 38-49
        • Musazzi L.
        • Treccani G.
        • Popoli M.
        Functional and structural remodeling of glutamate synapses in prefrontal and frontal cortex induced by behavioral stress.
        Front Psychiatry. 2015; 6: 60
        • Bollinger J.L.
        • Horchar M.J.
        • Wohleb E.S.
        Diazepam limits microglia-mediated neuronal remodeling in the prefrontal cortex and associated behavioral consequences following chronic unpredictable stress.
        Neuropsychopharmacology. 2020; 45: 1766-1776
        • Crider A.
        • Feng T.
        • Pandya C.D.
        • Davis T.
        • Nair A.
        • Ahmed A.O.
        • et al.
        Complement component 3a receptor deficiency attenuates chronic stress-induced monocyte infiltration and depressive-like behavior.
        Brain Behav Immun. 2018; 70: 246-256
        • Marques T.R.
        • Ashok A.H.
        • Pillinger T.
        • Veronese M.
        • Turkheimer F.E.
        • Dazzan P.
        • et al.
        Neuroinflammation in schizophrenia: Meta-analysis of in vivo microglial imaging studies.
        Psychol Med. 2019; 49: 2186-2196
        • Bale T.L.
        • Epperson C.N.
        Sex differences and stress across the lifespan.
        Nat Neurosci. 2015; 18: 1413-1420
        • Hodes G.E.
        • Pfau M.L.
        • Purushothaman I.
        • Ahn H.F.
        • Golden S.A.
        • Christoffel D.J.
        • et al.
        Sex differences in nucleus accumbens transcriptome profiles associated with susceptibility versus resilience to subchronic variable stress.
        J Neurosci. 2015; 35: 16362-16376
        • Howes O.D.
        • Hird E.J.
        • Adams R.A.
        • Corlett P.R.
        • McGuire P.
        Aberrant salience, information processing, and dopaminergic signaling in people at clinical high risk for psychosis.
        Biol Psychiatry. 2020; 88: 304-314
        • Chung D.W.
        • Wills Z.P.
        • Fish K.N.
        • Lewis D.A.
        Developmental pruning of excitatory synaptic inputs to parvalbumin interneurons in monkey prefrontal cortex.
        Proc Natl Acad Sci U S A. 2017; 114: E629-E637
        • Chung D.W.
        • Chung Y.
        • Bazmi H.H.
        • Lewis D.A.
        Altered ErbB4 splicing and cortical parvalbumin interneuron dysfunction in schizophrenia and mood disorders.
        Neuropsychopharmacology. 2018; 43: 2478-2486
        • Dienel S.J.
        • Enwright 3rd, J.F.
        • Hoftman G.D.
        • Lewis D.A.
        Markers of glutamate and GABA neurotransmission in the prefrontal cortex of schizophrenia subjects: Disease effects differ across anatomical levels of resolution.
        Schizophr Res. 2020; 217: 86-94
        • Gomez-Arboledas A.
        • Acharya M.M.
        • Tenner A.J.
        The role of complement in synaptic pruning and neurodegeneration.
        Immunotargets Ther. 2021; 10: 373-386
        • Shaw P.
        • Greenstein D.
        • Lerch J.
        • Clasen L.
        • Lenroot R.
        • Gogtay N.
        • et al.
        Intellectual ability and cortical development in children and adolescents.
        Nature. 2006; 440: 676-679
        • Veronese M.
        • Santangelo B.
        • Jauhar S.
        • D’Ambrosio E.
        • Demjaha A.
        • Salimbeni H.
        • et al.
        A potential biomarker for treatment stratification in psychosis: Evaluation of an [18 F] FDOPA PET imaging approach.
        Neuropsychopharmacology. 2021; 46: 1122-1132
        • Howes O.D.
        • Kapur S.
        A neurobiological hypothesis for the classification of schizophrenia: Type A (hyperdopaminergic) and type B (normodopaminergic).
        Br J Psychiatry. 2014; 205: 1-3
        • Tikka T.
        • Fiebich B.L.
        • Goldsteins G.
        • Keinänen R.
        • Koistinaho J.
        Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia.
        J Neurosci. 2001; 21: 2580-2588
        • Giovanoli S.
        • Engler H.
        • Engler A.
        • Richetto J.
        • Feldon J.
        • Riva M.A.
        • et al.
        Preventive effects of minocycline in a neurodevelopmental two-hit model with relevance to schizophrenia.
        Transl Psychiatry. 2016; 6: e772
        • Chaudhry I.B.
        • Hallak J.
        • Husain N.
        • Minhas F.
        • Stirling J.
        • Richardson P.
        • et al.
        Minocycline benefits negative symptoms in early schizophrenia: A randomised double-blind placebo-controlled clinical trial in patients on standard treatment.
        J Psychopharmacol. 2012; 26: 1185-1193
        • Solmi M.
        • Veronese N.
        • Thapa N.
        • Facchini S.
        • Stubbs B.
        • Fornaro M.
        • et al.
        Systematic review and meta-analysis of the efficacy and safety of minocycline in schizophrenia.
        CNS Spectr. 2017; 22: 415-426