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Integrating the neurodevelopmental and dopamine hypotheses of schizophrenia and the role of cortical excitation-inhibition balance.

  • Oliver D. Howes
    Correspondence
    Corresponding Author: Prof Oliver Howes, Department of Psychosis Studies, Institute of Psychiatry, Psychology, & Neuroscience, King’s College London, 16 De Crespigny Park, London SE5 8AB, UK
    Affiliations
    Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK

    Department of Psychosis, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, UK
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  • Ekaterina Shatalina
    Affiliations
    Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK
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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 pathoaetiology of schizophrenia but were developed in isolation. However, since they were originally proposed, there have been considerable advances in understanding of the normal neurodevelopmental refinement of synapses, and cortical excitatory-inhibitory (E/I) balance, as well as preclinical findings on the inter-relationship between cortical and sub-cortical 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 and glutamatergic signalling, as well as neurodevelopmental processes. Moreover, in vivo studies on the effects of stress, particularly during later development, show 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.
      Taken together, this integrated neurodevelopmental and dopamine hypothesis suggests overpruning of synapses, potentially including glutamatergic inputs onto frontal cortical interneurons, disrupts excitation-inhibition balance to underlie 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

      Introduction

      Schizophrenia is a common and disabling mental illness that is associated with psychotic, negative and cognitive symptoms, such as impairments in executive function and working memory (
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      • Howes O.D.
      Schizophrenia—an overview.
      ). Two key hypotheses for schizophrenia pathoetiology are the dopamine (
      • Howes O.D.
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      The dopamine hypothesis of schizophrenia: version III--the final common pathway.
      ), and neurodevelopmental hypotheses (
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      ,
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      ). The latter has recently been reframed as the sociodevelopmental hypothesis to account for the key role that psychosocial factors play in the developmental processes underlying schizophrenia (
      • Murray R.M.
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      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 excitatory-inhibitory balance in schizophrenia, studies modelling synaptic pruning mechanisms, genome-wide association studies and novel imaging techniques localising synaptic markers, show how these hypotheses may be integrated with previous work on excitation-inhibition balance (
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      ). Here, we first review normal synaptic development, and evidence for neurodevelopmental abnormalities in schizophrenia, before considering the evidence for excitation-inhibition imbalance in schizophrenia, and then propose a new integrative hypothesis that ties together dopaminergic dysfunction with the neuro(socio)developmental hypothesis of schizophrenia.

      Synaptic dynamics during neurodevelopment

      In rodents and non-human primates, studies show 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 (
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      ). Importantly, these developmental stages occur at different timepoints for different brain regions, in a caudo-rostral manner, with the somatosensory and visual regions amongst the first to reach synaptic stability and the frontal cortex developing last (
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      Comparing development of synaptic proteins in rat visual, somatosensory, and frontal cortex.
      ).
      Human post-mortem brain samples assessed by electron microscopy (
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      ) 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 (
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      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 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 also been directly aligned with rodent V1, with synaptic protein expression data suggesting development continues into late childhood (
      • Pinto J.G.
      • Jones D.G.
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      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 grey matter volumes increase rapidly during childhood followed by reductions during puberty and early adolescence (
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      ). Importantly, different brain regions differ in when grey matter markers reach their peak, start to fall and then stabilize, with higher-order association areas such as the dorsolateral prefrontal cortex maturing later than sensory areas (
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      Neurodevelopmental trajectories of the human cerebral cortex.
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      Age-related changes in grey and white matter structure throughout adulthood.
      ,
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      • Greenstein D.
      • Vaituzis A.C.
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      Dynamic mapping of human cortical development during childhood through early adulthood.
      ), showing the same pattern of temporo-regional 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 post-mortem studies of synaptic measures (
      • 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 compared to controls (
      • Zakharova N.
      • Mamedova G.S.
      • Bravve L.
      • Kaydan M.
      • Syunyakov T.
      • Kostyuk G.
      • et al.
      Brain gyrification index in schizophrenia (review, systematic review and meta-analysis).
      ). Specifically, patients have been reported to have reduced folding of the anterior cingulate cortex (ACC) (
      • Zakharova N.
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      • Bravve L.
      • Kaydan M.
      • Syunyakov T.
      • Kostyuk G.
      • et al.
      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 frontal cortex (
      • Narr K.L.
      • Thompson P.M.
      • Sharma T.
      • Moussai J.
      • Zoumalan C.
      • Rayman J.
      • et al.
      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 grey matter volumes, in particular, in the frontal cortex, relative to controls (
      • 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 grey matter exceeding normal age-related changes in schizophrenia indicates a neurodegenerative 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.
      ,
      • 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.
      ). Grey matter reduction in the absence of neuronal loss is consistent the loss of synapses, but it is important to recognise that other changes could contribute to grey 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 greater grey 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 there is at least a component of grey matter changes that occurs once the illness has developed. There have now been a number of longitudinal studies testing this further by measuring changes in grey matter volumes over the course of illness from the first episode of psychosis (FEP) (
      • 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 have found patients show accelerated reductions in grey 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.
      • Pol H.E.H.
      Heritability of changes in brain volume over time in twin pairs discordant for schizophrenia.
      ) and to matched healthy controls (
      • Brans R.G.
      • van Haren N.E.
      • van Baal G.C.M.
      • Schnack H.G.
      • Kahn R.S.
      • 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.
      • et al.
      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 grey matter changes. However, follow up of patients that start treatment suggests that while medication may have some contribution to grey matter reductions, an appreciable component of grey 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.
      ).
      Taken together, the gyrification and grey matter findings thus 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 do 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

      Post-mortem 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 mRNA levels in post-mortem samples from patients with schizophrenia relative to healthy controls, specifically in the hippocampus, frontal and cingulate cortices (
      • Osimo E.F.
      • Beck K.
      • 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 post-synaptic density markers also identified reductions in synaptic markers in frontal regions in schizophrenia relative to controls (
      • Berdenis van Berlekom A.
      • Muflihah C.H.
      • Snijders G.
      • 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 ubiquitously expressed in synaptic vesicles 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.
      • et al.
      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, two studies have been published comparing chronic patients with schizophrenia with controls. Both showed significantly lower SV2A density in the patient groups in the frontal and anterior cingulate cortices (
      • 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 post-mortem studies, thus, provide evidence for a failure to form and/or loss of synapses in schizophrenia in frontal cortex, and potentially other brain regions. Moreover, further analyses have shown there is 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.
      ). Work 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 iPSCs were cultured from patients with schizophrenia compared to those cultured from matched controls (
      • 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, whilst 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 post-mortem and in vivo lines of evidence indicate altered synaptic elimination in the frontal cortex may affect excitatory (glutamatergic) synapses. However, as GABA was not measured in the in vivo study, further work is required to determine if inhibitory terminals are also affected, and, if so, how this compares to glutamatergic effects in vivo. In view of this, we now consider excitatory-inhibitory balance and how it may be altered in schizophrenia.

      Excitatory-inhibitory balance

      Excitatory-inhibitory (E/I) balance refers to the relative contribution of excitatory and inhibitory synaptic inputs to brain signalling (
      • 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 neurones, localised 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 caudo-rostral manner, following a similar trajectory to synaptic markers during brain development described above, 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 signalling, whilst achieving a high cortical signal to noise ratio (
      • Froemke R.C.
      Plasticity of cortical excitatory-inhibitory balance.
      ). These 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., (2011) have shown that synaptic elimination is facilitated by microglia (
      • 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.
      ). 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.
      • et al.
      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 behaviour (
      • 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

      Genome-wide association studies (GWAS) have shown that schizophrenia is a polygenic disorder, with multiple low-penetrance variants contributing to the genetic risk for schizophrenia (
      • McCutcheon R.A.
      • Marques T.R.
      • Howes O.D.
      Schizophrenia—an overview.
      ). One of the most significant genetic associations with schizophrenia implicates genes of the major histocompatibility locus (MHC) locus encoding adaptive immune system components. This in part arises from the presence of many structurally diverse alleles of a complement protein (C4A) that 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.
      ). As well as this, several other genes with roles in microglia-mediated pruning have been identified in GWAS (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 summarised in table 1 and with further detail in supplementary table 1.
      Table 1Loci associated with schizophrenia identified by genome wide association studies (GWAS) that have a functional role in excitatory and inhibitory signalling or synaptic pruning.
      Gene (protein)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 alpha 1D subunit
      CACNA1Calcium Voltage-Gated Channel Subunit Alpha1 I, T-type calcium channel subunit, involved in neuronal calcium signalling
      CACNB2Voltage-dependent L-type calcium channel subunit beta-2, Component of a calcium channel complex, involved in neuronal calcium signalling
      DLG2Discs large MAGUK scaffold protein 2 (DLG2) is part of the postsynaptic protein scaffold of excitatory synapses, and involved in NMDA signalling
      FLOT1Flotillin-1 (FLOT1) enhances the formation of glutamatergic synapses but not GABAergic synapses (
      • Howes O.D.
      • Kapur S.
      The dopamine hypothesis of schizophrenia: version III--the final common pathway.
      ). Flot1 has been shown to be essential for amphetamine-induced reverse transport of DA in neurons but not for DA uptake (
      • McCutcheon R.A.
      • Marques T.R.
      • Howes O.D.
      Schizophrenia—an overview.
      )
      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 signalling
      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 (
      • McCutcheon R.A.
      • Marques T.R.
      • Howes O.D.
      Schizophrenia—an overview.
      ). It promotes stability of somatodendritic GABAergic synapses in vitro and in vivo through opposing endocytosis of GABA-A receptors (
      • Howes O.D.
      • Kapur S.
      The dopamine hypothesis of schizophrenia: version III--the final common pathway.
      )
      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 GABA-A-mediated synaptic transmission.
      GABBR1Gamma-Aminobutyric Acid Type B Receptor Subunit 1
      GABBR2Gamma-Aminobutyric Acid Type B Receptor Subunit 2
      PLCL1Phospholipase C Like 1 regulates the turnover of GABA-A 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 synaptic development
      CUL3Culin-3 is compartmentalized at postsynaptic densities and gates retrograde signalling, it is involved in neural development, neurotransmission, and maintaining excitation-inhibition (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 neurones
      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.
      Key loci associated with schizophrenia risk linked to excitatory neurotransmission include components of the NMDA receptor (Subunit 2A), 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 (SRR), which catalyses synthesis of the glutamate co-agonist, D-serine, as well as genes encoding components of post-synaptic protein scaffold of excitatory synapses, including post-synaptic density protein 93 (PSD-93) and SYNGAP1, which is thought to be involved in NMDA-R-dependent control of AMPA-R 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 GABA-B 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 ANK3 (Ankyrin-G), which promotes stability of somatodendritic GABA-ergic 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.
      ,
      Consortium SPG-WAS
      Genome-wide association study identifies five new schizophrenia loci.
      ,
      • Bergen S.
      • O'dushlaine C.
      • Ripke S.
      • Lee P.
      • Ruderfer D.
      • 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 GABA-ergic transmission also influences expression of GABA-A receptor components and has been implicated in schizophrenia GWAS 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.
      ,
      Consortium SPG-WAS
      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, summarised in figure 2, indicate that genetic risk for schizophrenia affects proteins involved in both excitatory and inhibitory signalling, which together could predispose an individual to E/I imbalance, although the direction of the imbalance cannot be inferred based on genetics 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, as 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 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, iPSC findings 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 grey matter volume changes in the prodrome and early phase of illness. Based on these findings, we propose that there is also aberrant synaptic pruning both early and later in neurodevelopment, leading to overpruning of synapses and excitatory/inhibitory imbalance and schizophrenia. Further patient studies are required to determine the course of synaptic loss.
      Figure thumbnail gr2
      Figure 2Genes encoding inhibitory and excitatory signalling components identified by schizophrenia genome-wide association studies associated with schizophrenia risk. GRM3 - Glutamate Metabotropic Receptor 3, AKT3 - AKT serine/threonine kinase 3, DLG2 - Discs large MAGUK scaffold protein 2, GRI2A - Glutamate Ionotropic Receptor NMDA Type Subunit 2A, GRIA1 - Glutamate Ionotropic Receptor AMPA Type Subunit 1, SYNGAP1 - Synaptic Ras GTPase Activating Protein 1, HCN1 - hyperpolarization-activated cyclic nucleotide-gated channel component, SRR - Serine racemase, CACNB2 - Voltage-dependent L-type calcium channel subunit beta-2, CACNA1 - Calcium Voltage-Gated Channel Subunit Alpha1 I, GABBR - Gamma-Aminobutyric Acid Type B Receptor, ANK3 - Ankyrin-G/ankyrin-3, PLCL1 - Phospholipase C Like 1, CLCN3 - Chloride Voltage-Gated Channel 3, SLC31A1 - Solute Carrier Family 32 Member 1.
      Figure thumbnail gr3
      Figure 3Aberrant excitatory-inhibitory balance in the frontal cortex of patients with schizophrenia. Lower levels of excitatory synaptic inputs onto inhibitory interneurons (shown in green) result in increased activity of pyramidal neurons (shown in orange, arrows indicate activity).

      In vivo evidence for altered E/I balance in schizophrenia

      Electroencephalography (EEG) and magnetoencephalography (MEG) 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 signalling (
      • 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.
      • et al.
      Gamma band oscillations in the early phase of psychosis: A systematic review.
      ,
      • Grent 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 GABA-B receptors which are located on glutamatergic afferents and inhibit pyramidal neuron firing (
      • De Wilde O.
      • Bour L.J.
      • Dingemans P.M.
      • Koelman J.
      • Linszen D.
      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.
      • 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 GABA-A, GABA-B and NMDA-mediated activity, using paradigms such as short interval intracortical inhibition (SICI), long interval intracortical inhibition (LICI) and intracortical facilitation (ICF), respectively (
      • Cash R.F.
      • Noda Y.
      • Zomorrodi R.
      • Radhu N.
      • Farzan F.
      • Rajji T.K.
      • et al.
      Characterization of glutamatergic and GABA A-mediated neurotransmission in motor and dorsolateral prefrontal cortex using paired-pulse TMS–EEG.
      ) (additional details in supplement). These responses have been shown to be reduced in patients with schizophrenia in comparison to controls (
      • 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 measures, the mismatch negativity (MMN) response, is dependent on intact NMDA receptor signalling (
      • 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.
      ). Meta-analysis shows MMN is lower in patients with schizophrenia compared to healthy controls 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.
      ), with a recent study showing reduced MMN amplitude was associated with reduced glutamate levels in this patient group, measured with magnetic resonance spectroscopy (
      • 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 NMDA receptor 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, post-mortem 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 above 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 MEG/EEG signal. Computational modelling of EEG data from schizophrenia patients suggests 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 with 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 SICI responses are correlated with cognitive function in schizophrenia (
      • Noda Y.
      • Barr M.S.
      • Zomorrodi R.
      • Cash R.F.
      • 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 NMDA-R antagonist, to non-human primates. These resembled deficits seen in schizophrenia and were accompanied by decreased inhibitory interneuron and increased excitatory activity in lateral prefrontal cortex (
      • 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.
      ). These findings, thus, indicate that E/I imbalance could underlie cognitive impairments in schizophrenia. We consider the key question of how these cortical impairments may also lead to psychotic symptoms in the following sections.

      Dopamine abnormalities in schizophrenia

      Multiples lines of evidence from genetic, post-mortem, 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 D2/3 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.
      • et al.
      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.
      • Kolachana B.
      • 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 (
      • 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.
      • 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 studies; 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.
      • et al.
      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.
      • Carter C.
      • Kerwin R.
      Effect of 6‐hydroxydopamine lesions of the medial prefrontal cortex on neurotransmitter systems in subcortical sites in the rat.
      ,
      • Pycock C.
      • Kerwin R.
      • Carter C.
      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 prefrontal cortex (mPFC) results in striatal dopamine release both directly through excitatory afferents (
      • Quiroz C.
      • Orru M.
      • Rea W.
      • Ciudad-Roberts A.
      • Yepes G.
      • Britt J.P.
      • et al.
      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.
      • Orru M.
      • Rea W.
      • Ciudad-Roberts A.
      • Yepes G.
      • Britt J.P.
      • et al.
      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.
      • Ferre 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 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 frontal cortical-VTA/SNc circuitry (
      • 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.
      ). The study also showed that both frontal optogenetic stimulation and progressive cortical synaptic loss lead to hyperlocomotion as well as 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.
      ).
      NMDA-R 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 sub-chronic 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 DA 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.
      ). Sub-chronic 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.
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      • Katsuki F.
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      Optogenetic manipulation of an ascending arousal system tunes cortical broadband gamma power and reveals functional deficits relevant to schizophrenia.
      ).
      In healthy controls a single dose of ketamine increases amphetamine-induced striatal dopamine release (
      • Kegeles L.S.
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      • 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 grey 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 (18)F-DOPA PET and voxel-based morphometry study.
      ). Furthermore, N-acetylaspartate (NAA) levels in the dorsolateral PFC were associated with greater amphetamine-induced release of striatal dopamine in patients with schizophrenia, but not in healthy controls (
      • 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 NAA levels are associated with neuronal dysfunction (
      • Whitehurst T.S.
      • Osugo M.
      • Townsend L.
      • Shatalina E.
      • Vava R.
      • Onwordi E.C.
      • et al.
      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 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.
      • Allen P.
      • Broome M.
      • Valli I.
      • Asselin M.
      • 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 controls (
      • 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 excitatory-inhibitory balance and synaptic density

      Rodent studies show 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 prefrontal cortex (PFC) and changes in E/I molecular markers (
      • Albrecht A.
      • Ivens S.
      • Papageorgiou I.E.
      • Caliskan G.
      • Saiepour N.
      • Bruck 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.
      • Caliskan G.
      • Saiepour N.
      • Bruck 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-Gomez E.
      • et al.
      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 remodelling suggest 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 also 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 microglia may mediate aberrant synaptic pruning that lead to E/I imbalance.
      Interestingly, numerous rodent studies show effects on E/I balance and enhanced microglial pruning and resultant synaptic loss are more marked in males (
      • 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-Gomez E.
      • et al.
      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 women (
      • McCutcheon R.A.
      • Marques T.R.
      • 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, 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 signalling. 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 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. This is anticipated to lead to increased noise in cortical circuits, impairing cortical function and lead to the cognitive and negative symptoms of the disorder. We propose this also disinhibits excitatory projections that regulate mesostriatal dopamine neurons, resulting in dopamine dysregulation and psychotic symptoms through disrupting prediction error signalling (for 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 gr4
      Figure 4Projections from the frontal cortex to the striatum and midbrain origin of dopamine neurons. Frontal excitatory-inhibitory (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.
      Figure thumbnail gr5
      Figure 5Integrative hypothesis showing how excitatory-inhibitory (E/I) imbalance could lead to onset of cognitive (e.g. impairments in working memory, processing speed, executive function) and negative symptoms (e.g. depression, flattening of emotions) of schizophrenia, as well as to striatal dopaminergic dysfunction, which underlies psychotic symptoms.
      The timing of these processes fit with the time course for the development of symptoms, which typically begin with cognitive impairments, 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 if 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. Key questions are, thus, the precise localization of E/I imbalance within cortical circuitry, the direction of the shift in E/I at different developmental timepoints, 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 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 if 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 III, 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 if 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 signalling contribute to adaptive compensatory change or towards pathology. Additionally, 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, whilst 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 if 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 modelling circuit formation may be useful to better model this developmental stage in schizophrenia. It should also be recognised 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, whilst, as we have highlighted, there are data showing 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 leads to striatal hyperactivity via PFC overactivity and if overpruning in schizophrenia may continue into adulthood.
      Lastly, stress is a risk factor for many other psychiatric disorders. Why then does this 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 recognised that, whilst 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 ideas that there are neurobiological sub-types 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 pro-cognitive compounds that could do this in development, 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.
      ), synaptic vesicle proteins (Syndesi Therapeutics), or GABA and nicotinic systems (Recognify Life Sciences).
      Another novel treatment pathway is to address aberrant pruning. Minocycline is an antibiotic which inhibits microglial activation, amongst 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 behavioural 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 cohort 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 more specific treatments may be needed.

      Conclusions

      Schizophrenia is associated with a genetic predisposition affecting proteins involved in excitatory and inhibitory signalling and with post-mortem and in vivo evidence for this. Evidence of lower synaptic density and as progressive grey matter changes in the disorder, suggest 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 signalling suggests this process may then underlie the eventual onset of psychotic symptoms. In vivo evidence shows 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 developing schizophrenia. Together, this model ties the neurodevelopmental and dopamine hypotheses of schizophrenia into a single pathoaetological hypothesis and identifies preventative therapies targeting pruning or those correcting frontal E/I imbalance as important future avenues for research.

      Acknowledgements

      The authors would like to thank Dr. Robert McCutcheon for critical reading of the manuscript

      Supplementary Material

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