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Review
. 2020 Dec 1;177(12):1119-1128.
doi: 10.1176/appi.ajp.2020.20101481.

Fifty Years of Research on Schizophrenia: The Ascendance of the Glutamatergic Synapse

Joseph T Coyle  1 , W Brad Ruzicka  1 , Darrick T Balu  1
Affiliations
Review

Fifty Years of Research on Schizophrenia: The Ascendance of the Glutamatergic Synapse

Joseph T Coyle et al. Am J Psychiatry. .
No abstract available

Keywords: Antipsychotics; Genetics/Genomics; History of Psychiatry; Neuropathology; Schizophrenia Spectrum and Other Psychotic Disorders.

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Figures

FIGURE 1.
FIGURE 1.. Genetic risk for schizophrenia converges on the glutamatergic synapsea
a Genome-wide association studies of large numbers of individuals have identified over 100 schizophrenia-associated risk genes (55), and exome sequencing of many thousands of cases identified 10 ultra-rare coding mutations significantly associated with schizophrenia risk (56). Both of these lines of genetic evidence indicate a prominent role of the glutamatergic synapse in schizophrenia pathology. The selected schizophrenia risk genes shown here demonstrate the relevance of all aspects of the excitatory synapse to schizophrenia. At the presynaptic terminal, genes including SNCA (synuclein alpha) and SNAP91 (synaptosome associated protein 91) regulate synaptic vesicle trafficking. Transsynaptic cell adhesion molecules such as PTPRF (Protein Tyrosine Phosphatase Receptor Type F) and LRRC4B (Leucine Rich Repeat Containing 4B) regulate synaptic signaling, establishment, and remodeling. Multiple nonreceptor ion channel subunit genes are associated with schizophrenia, including calcium channel subunits CACNA1C, CACNA1D, and CACNA1G and chloride ion channel subunit CLCN3. Similarly, subunits of glutamate receptors are themselves encoded by schizophrenia risk genes, including NMDA receptor subunit GRIN2A, AMPA receptor subunits GRIA1 and GRIA3, and metabotropic glutamate receptors GRM1 and GRM3. The serine racemase enzyme (SRR) converts l-serine to d-serine, the primary co-agonist of NMDA receptors. Complement component C4, encoded by the C4A and C4B genes within the major histocompatibility complex locus, contributes to excessive pruning of excitatory synapses and the decreased density of dendritic spines observed in schizophrenia. Finally, multiple nuclear factors, including the transcription factor MEF2C, regulate gene expression serving to mediate glutamatergic neurotransmission.
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