UNIGE document Scientific Article
previous document  unige:111010  next document
add to browser collection
Title

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

Authors
Lander, Sharon S
Khan, Usman
Lewandowski, Nicole
Chakraborty, Darpan
Provenzano, Frank A
Mingote, Susana
Chornyy, Sergiy
show hidden authors show all authors [1 - 13]
Published in Schizophrenia Bulletin. 2019, vol. 45, no. 1, p. 127-137
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. 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.
Identifiers
PMID: 29471549
Full text
Article (Published version) (1 MB) - document accessible for UNIGE members only Limited access to UNIGE
Structures
Research group Mitochondries et sécrétion d'insuline (671)
Project
FNS: #146984
Citation
(ISO format)
LANDER, Sharon S et al. Glutamate Dehydrogenase-Deficient Mice Display Schizophrenia-Like Behavioral Abnormalities and CA1-Specific Hippocampal Dysfunction. In: Schizophrenia Bulletin, 2019, vol. 45, n° 1, p. 127-137. doi: 10.1093/schbul/sby011 https://archive-ouverte.unige.ch/unige:111010

196 hits

0 download

Update

Deposited on : 2018-11-20

Export document
Format :
Citation style :