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Why Hippocampal Glutamate Levels Are Elevated in Schizophrenia

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1 Credit CME

Recently completed genetic studies,1,2 the largest and most comprehensive of their kind, help resolve schizophrenia’s complex pathobiology. With a preponderance of implicated genes localizing to hippocampal glutamatergic neurons, in particular pathogenic loss-of-function mutations in subunits of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) glutamate receptors, the genetics inform the disorder’s anatomy and its pathophysiology.

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Article Information

Corresponding Author: Scott A. Small, MD, 630 W 168th St, New York, NY 10032 (sas68@columbia.edu).

Published Online: January 25, 2023. doi:10.1001/jamapsychiatry.2022.3849

Conflict of Interest Disclosures: Dr Small reported other support from Tesarakt and patent pending 63/175,872, docket 01001/009746-US3 and is a cofounder of, consultant for, and equity holder of Retromer Therapeutics. Dr Guo reported being a 10% equity holder as the cofounder of Tesarakt and the following patents pending: 63/255,196 docket 01001/009746-US2; 63/304,211 docket 3970-0031PV01; 63/289,785 docket 3970-0046PV04; 63/404,667 docket 3970-0054PV01; 63/293,290 docket 3970-0047PV01, and US20210150671A1. No other disclosures were reported.

References
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2.
Trubetskoy  V , Pardiñas  AF , Qi  T ,  et al; Indonesia Schizophrenia Consortium; PsychENCODE; Psychosis Endophenotypes International Consortium; SynGO Consortium; Schizophrenia Working Group of the Psychiatric Genomics Consortium.  Mapping genomic loci implicates genes and synaptic biology in schizophrenia.   Nature. 2022;604(7906):502-508. doi:10.1038/s41586-022-04434-5 PubMedGoogle ScholarCrossref
3.
Small  SA , Schobel  SA , Buxton  RB , Witter  MP , Barnes  CA .  A pathophysiological framework of hippocampal dysfunction in ageing and disease.   Nat Rev Neurosci. 2011;12(10):585-601. doi:10.1038/nrn3085 PubMedGoogle ScholarCrossref
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Schobel  SA , Chaudhury  NH , Khan  UA ,  et al.  Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver.   Neuron. 2013;78(1):81-93. doi:10.1016/j.neuron.2013.02.011 PubMedGoogle ScholarCrossref
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Brenner  E , Kondziella  D , Håberg  A , Sonnewald  U .  Impaired glutamine metabolism in NMDA receptor hypofunction induced by MK801.   J Neurochem. 2005;94(6):1594-1603. doi:10.1111/j.1471-4159.2005.03311.x PubMedGoogle ScholarCrossref
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Lander  SS , Khan  U , Lewandowski  N ,  et al.  Glutamate dehydrogenase-deficient mice display schizophrenia-like behavioral abnormalities and CA1-specific hippocampal dysfunction.   Schizophr Bull. 2019;45(1):127-137. doi:10.1093/schbul/sby011 PubMedGoogle ScholarCrossref
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Gaisler-Salomon  I , Miller  GM , Chuhma  N ,  et al.  Glutaminase-deficient mice display hippocampal hypoactivity, insensitivity to pro-psychotic drugs and potentiated latent inhibition: relevance to schizophrenia.   Neuropsychopharmacology. 2009;34(10):2305-2322. doi:10.1038/npp.2009.58 PubMedGoogle ScholarCrossref
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