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Imaging Patients with Psychosis and a Mouse Model Establishes a Spreading Pattern of Hippocampal Dysfunction and Implicates Glutamate as a Driver

Department of Psychiatry, Columbia University Medical Center, New York, NY, USA.
Elsevier Science
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Neuron. 2013 Apr 10;78(1):81-93.
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Appears in Collections:
R01 MH093398/MH/NIMH NIH HHS/United States
K23 MH066279/MH/NIMH NIH HHS/United States
K23 MH090563/MH/NIMH NIH HHS/United States
P40 HD003110/HD/NICHD NIH HHS/United States
P50 MH086385/MH/NIMH NIH HHS/United States
R21 MH086125/MH/NIMH NIH HHS/United States
U54 EB005149/EB/NIBIB NIH HHS/United States
UL1 RR024156/RR/NCRR NIH HHS/United States
UL1 TR000040/TR/NCATS NIH HHS/United States
Generated Citation:
Schobel S.A., Chaudhury N.H., Khan U.A., Paniagua B., Styner M., Asllani I., Inbar B.P., Corcoran C.M., Lieberman J.A., Moore H., Small S.A. Imaging Patients with Psychosis and a Mouse Model Establishes a Spreading Pattern of Hippocampal Dysfunction and Implicates Glutamate as a Driver. Neuron. 2013 Apr 10;78(1):81-93. PMID: 23583108. PMCID: PMC3966570.
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The hippocampus in schizophrenia is characterized by both hypermetabolism and reduced size. It remains unknown whether these abnormalities are mechanistically linked. Here we addressed this question by using 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 occurred 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 similar regional pattern of hypermetabolism, while repeated exposure shifted the hippocampus to a hypermetabolic basal state with concurrent atrophy and pathology in parvalbumin-expressing interneurons. Parallel in vivo experiments using the glutamate-reducing drug 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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