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Psychiatry and Behavioral Health

Why Hippocampal Glutamate Levels Are Elevated in Schizophrenia

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JAMA Psychiatry

Published Online: January 25, 2023

Neuroscience and Psychiatry

Article Information and Disclosures

Jia Guo, PhD¹;

Douglas L. Rothman, PhD²;

Scott A. Small, MD¹

Author Affiliations

¹Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Mortimer B. Zuckerman Mind Brain Behavior Institute, Departments of Neurology and Psychiatry, Columbia University, New York, New York
²Yale University School of Medicine, Department of Radiology and Biomedical Imaging and Department of Biomedical Engineering, Yale University, New Haven, Connecticut

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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

Singh T , Poterba T , Curtis D , et al. Rare coding variants in ten genes confer substantial risk for schizophrenia. Nature. 2022;604(7906):509-516. doi:10.1038/s41586-022-04556-w PubMed Google Scholar Crossref

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 PubMed Google Scholar Crossref

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 PubMed Google Scholar Crossref

Talati P , Rane S , Kose S , et al. Increased hippocampal CA1 cerebral blood volume in schizophrenia. Neuroimage Clin. 2014;5:359-364. doi:10.1016/j.nicl.2014.07.004 PubMed Google Scholar Crossref

Merritt K , McGuire PK , Egerton A , et al; 1H-MRS in Schizophrenia Investigators. Association of age, antipsychotic medication, and symptom severity in schizophrenia with proton magnetic resonance spectroscopy brain glutamate level. JAMA Psychiatry. 2021;78(6):667-681. doi:10.1001/jamapsychiatry.2021.0380 PubMed Google Scholar Crossref

Provenzano FA , Guo J , Wall MM , et al. Hippocampal pathology in clinical high-risk patients and the onset of schizophrenia. Biol Psychiatry. 2020;87(3):234-242. doi:10.1016/j.biopsych.2019.09.022 PubMed Google Scholar Crossref

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 PubMed Google Scholar Crossref

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 PubMed Google Scholar Crossref

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 PubMed Google Scholar Crossref

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 PubMed Google Scholar Crossref

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