Glutamate Dehydrogenase–Deficient Mice Display Schizophrenia-Like Behavioral Abnormalities and CA1-Specific Hippocampal Dysfunction
| Autor: | Inna Gaisler-Salomon, Sergiy Chornyy, Hanoch Kaphzan, Sharon S Lander, Scott A. Small, Nicole M. Lewandowski, Frank A. Provenzano, Stephen Rayport, Francesca Frigerio, Susana Mingote, Darpan Chakraborty, Pierre Maechler, Usman A. Khan |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
medicine.medical_specialty Hippocampal formation Inhibitory postsynaptic potential 03 medical and health sciences Mice 0302 clinical medicine Glutamate Dehydrogenase Internal medicine Medicine Animals Cerebral Blood Volume ddc:612 CA1 Region Hippocampal Mice Knockout Behavior Animal business.industry Glutaminase Glutamate dehydrogenase Glutamate receptor Magnetic Resonance Imaging Pathophysiology 030227 psychiatry Psychiatry and Mental health Disease Models Animal Endocrinology Receptors Glutamate Excitatory postsynaptic potential Schizophrenia Female business Hypoactivity 030217 neurology & neurosurgery Regular Articles |
| Zdroj: | Schizophrenia Bulletin, Vol. 45, No 1 (2019) pp. 127-137 |
| ISSN: | 0586-7614 |
| Popis: | 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. Finally, in a direct clinical correlation using imaging-guided microarray, we found a significant SCZ-associated postmortem reduction in GLUD1 expression in CA1. These findings advance GLUD1 deficiency as a driver of excess hippocampal excitatory transmission and SCZ symptoms, and identify GDH as a target for glutamate modulation pharmacotherapy for SCZ. More broadly, these findings point to the likely involvement of alterations in glutamate metabolism in the pathophysiology of SCZ. |
| Databáze: | OpenAIRE |
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