Imaging Patients with Psychosis and a Mouse Model Establishes a Spreading Pattern of Hippocampal Dysfunction and Implicates Glutamate as a Driver
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SUMMARY The hippocampus in schizophrenia is characterized by both hypermetabolism and reduced size. It remains unknown whether these abnormalities are mechanistically linked. Here, in addressing these questions we used MRI tools that can map hippocampal metabolism and structure in patients and mouse models. In at-risk patients, hypermetabolism was found to begin in CA1 and spread to the subiculum after psychosis onset. CA1 hypermetabolism at baseline predicted hippocampal atrophy, which occured during progression to psychosis, most prominently in similar regions. Next, we used ketamine to model conditions of acute psychosis in mice. Acute ketamine reproduced a regional pattern of hippocampal hypermetabolism, while repeated exposure shifted the hippocampus to a hypermetabolic state with concurrent atrophy and pathology in parvalbumin-expressing interneurons. Parallel in vivo experiments using LY379268 and direct measurements of extracellular glutamate showed that glutamate drives both neuroimaging abnormalities. These findings show that hippocampal hypermetabolism leads to atrophy in psychotic disorder and suggest glutamate as a pathogenic driver.
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Psychosis has also been associated with increased hippocampal glutamate levels in humans.
“In humans, psychosis has also been associated with increased hippocampal glutamate levels 65,66 ,”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [66]
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- Authors
- Schobel, S. A., Chaudhury, N. H., Khan, U. A., Paniagua, B., Styner, M. A., Asllani, I., Inbar, B. P., Corcoran, C. M., Lieberman, J. A., Moore, H., & Small, S. A.
- Affiliations
- Columbia University Irving Medical Center (US)
- New York State Psychiatric Institute (US)
- State University of New York (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Moore, Holly
- Small, Scott A.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 78
- Issue
- 1
- Pages
- 81-93
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3966570
- OpenAlex
- W1984141645
- Cited by
- 549
- References
- 7
- Citations by year
- 2026: 18 · 2025: 39 · 2024: 33 · 2023: 39 · 2022: 40 · 2021: 44 · 2020: 43 · 2019: 38 · 2018: 39 · 2017: 75 · 2016: 48 · 2015: 42 · 2014: 37 · 2013: 10 · 2012: 2
- FWCI
- 32.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- Sidney R. Baer, Jr. Foundation
- Broitman Foundation
- National Institutes of Health (UL1TR000040, RR024156, TR000040)
- National Institute on Aging (R01AG025161, P50AG008702, K23AG000946)
- National Institute of Mental Health (MH086385, P50MH086385, K23MH066279, R01MH093398, K23MH090563, R21MH086125)
- National Institute of Biomedical Imaging and Bioengineering (U54EB005149)
- National Center for Research Resources (Grant Number UL1 RR024156, UL1RR024156)
- National Center for Advancing Translational Sciences (TR000040)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P40HD03110)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Keywords
- schizophrenia, psychosis, hippocampal atrophy, glutamate, ketamine, LY379268, parvalbumin interneurons, CA1, subiculum, neuroimaging, mouse model, transition to psychosis
- MeSH terms
- Amino Acids, Animals, Atrophy, Brain Mapping, Disease Models, Animal, Female, Follow-Up Studies, Hippocampus, Humans, Ketamine, Functional Laterality, Magnetic Resonance Imaging, Male, Mice, Inbred C57BL, Psychotic Disorders, Time Factors, Excitatory Amino Acid Agonists, Excitatory Amino Acid Antagonists, Glutamic Acid, Bridged Bicyclo Compounds, Heterocyclic, Imaging, Three-Dimensional, Mice
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