Abstract
Keywords
Introduction
Synaptic dynamics during neurodevelopment
Imaging evidence for aberrant neurodevelopment in schizophrenia
Evidence for aberrant synaptic density in schizophrenia
- Finnema S.J.
- Nabulsi N.B.
- Mercier J.
- Lin S-f
- Chen M.-K.
- Matuskey D.
- et al.
- Onwordi E.C.
- Whitehurst T.
- Mansur A.
- Statton B.
- Berry A.
- Quinlan M.
- et al.
Excitatory-inhibitory balance
Genetic risk and excitatory and inhibitory neurotransmission in schizophrenia
Gene (protein) | Functional role |
---|---|
Genes for proteins involved in excitatory neurotransmission | |
ADAM10 | ADAM 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 |
AKT3 | AKT 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. |
CACNA1 | Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents. |
CACNA1D | L-type voltage-gated calcium channel alpha 1D subunit |
CACNA1 | Calcium Voltage-Gated Channel Subunit Alpha1 I, T-type calcium channel subunit, involved in neuronal calcium signalling |
CACNB2 | Voltage-dependent L-type calcium channel subunit beta-2, Component of a calcium channel complex, involved in neuronal calcium signalling |
DLG2 | Discs large MAGUK scaffold protein 2 (DLG2) is part of the postsynaptic protein scaffold of excitatory synapses, and involved in NMDA signalling |
FLOT1 | Flotillin-1 (FLOT1) enhances the formation of glutamatergic synapses but not GABAergic synapses ( 2 ). Flot1 has been shown to be essential for amphetamine-induced reverse transport of DA in neurons but not for DA uptake (1 ) |
GRIA1 | Glutamate Ionotropic Receptor AMPA Type Subunit 1 |
GRIN2A | Glutamate Ionotropic Receptor NMDA Type Subunit 2A |
GRM3 | Glutamate Metabotropic Receptor 3 |
HCN1 | The hyperpolarization-activated cyclic nucleotide-gated (HCN1) channels modulate the rate of glutamate release by changing rate of exocytosis in synaptic terminals. |
RYR3 | Ryanodine receptor type 3 (RyR3) involved in Ca signalling |
SRR | Serine racemase catalyzes the synthesis of D-serine from L-serine. D-serine is a key coagonist with glutamate at NMDA receptors |
SYNGAP1 | Synaptic 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 | |
ANK3 | Ankyrin-G/ankyrin-3 (ANK3) is integral to AMPAR-mediated synaptic transmission and maintenance of spine morphology ( 1 ). It promotes stability of somatodendritic GABAergic synapses in vitro and in vivo through opposing endocytosis of GABA-A receptors (2 ) |
CLCN3 | Chloride 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. |
FURIN | Furin a protease enzyme is involved in GABA-A-mediated synaptic transmission. |
GABBR1 | Gamma-Aminobutyric Acid Type B Receptor Subunit 1 |
GABBR2 | Gamma-Aminobutyric Acid Type B Receptor Subunit 2 |
PLCL1 | Phospholipase 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. |
SLC32A1 | Solute 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 | |
ADAM10 | ADAM 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. |
CSMD1 | Regulator of C4 expression |
C4 | Complement component 4, protein expressed on synapses to tag them for elimination by microglia |
PDE4B | Phosphodiesterase 4B is a microglia target to reduce neuroinflammation. Also expressed at the synapse. |
VRK2 | Vaccinia-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 | |
AMBRA1 | Autophagy 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. |
CLSTN3 | Calsyntenin-3 promotes inhibitory and excitatory synaptic development synaptic development |
CUL3 | Culin-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. |
FOXP1 | Forkhead box protein 1 is a transcription factor for genes associated with synaptic function and development. |
GPM6A | Glycoprotein M6A contributes to spine and, likely, synapse formation |
HIP1R | Huntingtin-Interacting Protein 1-Related Protein plays a critical role in dendritic development and excitatory synapse formation in hippocampal neurones |
IGSF9B | Immunoglobulin Superfamily Member 9B is a transmembrane protein which is abundantly expressed in interneurons, where it may regulate inhibitory synapse development |
KALRN | Kalirin7 is involved in the formation of dendritic spines |
LRRTM4 | Leucine Rich Repeat Transmembrane Neuronal 4 is involved in regulating excitatory synapse development |
MEF2C | Myocyte 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. |
NLGN4X | Neuroligin 4 X-Linked is a member of the neuroligin family of proteins, which are involved in the regulation of excitatory synaptic transmission. |



In vivo evidence for altered E/I balance in schizophrenia
Dopamine abnormalities in schizophrenia
- Breier A.
- Su T.-P.
- Saunders R.
- Carson R.
- Kolachana B.
- De Bartolomeis A.
- et al.
Evidence cortical disruption leads to striatal dopamine overactivity
Effects of stress on excitatory-inhibitory balance and synaptic density
An integrated hypothesis


Outstanding issues
Implications for treating schizophrenia
Conclusions
Acknowledgements
Supplementary Material
References
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Oliver Howes 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 organised by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Jansenn, Lundbeck, Neurocrine, Otsuka, Sunovion, Recordati, Roche and Viatris/ Mylan. Neither Dr Howes or his family have holdings/ a financial stake in any pharmaceutical company. Dr Howes has a patent for the use of dopaminergic imaging.
Ekaterina Shatalina has reported 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.
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