Glutamate Dehydrogenase-Deficient Mice Display Schizophrenia-Like Behavioral Abnormalities and CA1-Specific Hippocampal Dysfunction

Schizophrenia Bulletin
Sharon S LanderInna Gaisler-Salomon

Abstract

Brain imaging has revealed that the CA1 subregion of the hippocampus is hyperactive in prodromal and diagnosed patients with schizophrenia (SCZ), and that glutamate is a driver of this hyperactivity. Strikingly, mice deficient in the glutamate synthetic enzyme glutaminase have CA1 hypoactivity and a SCZ-resilience profile, implicating glutamate-metabolizing enzymes. To address this further, we examined mice with a brain-wide deficit in the glutamate-metabolizing enzyme glutamate dehydrogenase (GDH), encoded by Glud1, which should lead to glutamate excess due to reduced glutamate metabolism in astrocytes. We found that Glud1-deficient mice have behavioral abnormalities in the 3 SCZ symptom domains, with increased baseline and amphetamine-induced hyperlocomotion as a positive symptom proxy, nest building and social preference as a negative symptom proxy, and reversal/extradimensional set shifting in the water T-maze and contextual fear conditioning as a cognitive symptom proxy. Neuroimaging of cerebral blood volume revealed hippocampal hyperactivity in CA1, which was associated with volume reduction. Parameters of hippocampal synaptic function revealed excess glutamate release and an elevated excitatory/inhibitory balance in CA1....Continue Reading

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Citations

Jul 19, 2018·The New England Journal of Medicine·Jeffrey A Lieberman, Michael B First
Nov 21, 2020·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Prudhvi Raj RayiHanoch Kaphzan
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