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Publication
Activating mGlu3 Metabotropic Glutamate Receptors Rescues Schizophrenia-like
Cognitive Deficits Through Metaplastic Adaptations Within the Hippocampus.
Authors Dogra S, Stansley BJ, Xiang Z, Qian W, Gogliotti RG, Nicoletti F, Lindsley CW,
Niswender CM, Joffe ME, Conn PJ
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal Biological Psychiatry
Year 2021
Date Published 9/1/2021
Volume : Pages 90 : 385 - 398
PubMed Reference 33965197
Abstract Polymorphisms in GRM3, the gene encoding the mGlu3 metabotropic glutamate
receptor, are associated with impaired cognition and neuropsychiatric disorders
such as schizophrenia. Limited availability of selective genetic and molecular
tools has hindered progress in developing a clear understanding of the
mechanisms through which mGlu3 receptors regulate synaptic plasticity and
cognition., We examined associative learning in mice with trace fear
conditioning, a hippocampal-dependent learning task disrupted in patients with
schizophrenia. Underlying cellular mechanisms were assessed using ex vivo
hippocampal slice preparations with selective pharmacological tools and
selective genetic deletion of mGlu3 receptor expression in specific neuronal
subpopulations., mGlu3 receptor activation enhanced trace fear conditioning and
reversed deficits induced by subchronic phencyclidine. Mechanistic studies
revealed that mGlu3 receptor activation induced metaplastic changes, biasing
afferent stimulation to induce long-term potentiation through an mGlu5
receptor-dependent, endocannabinoid-mediated, disinhibitory mechanism. Selective
genetic deletion of either mGlu3 or mGlu5 from hippocampal pyramidal cells
eliminated effects of mGlu3 activation, revealing a novel mechanism by which
mGlu3 and mGlu5 interact to enhance cognitive function., These data demonstrate
that activation of mGlu3 receptors in hippocampal pyramidal cells enhances
hippocampal-dependent cognition in control and impaired mice by inducing a novel
form of metaplasticity to regulate circuit function, providing a clear mechanism
through which genetic variation in GRM3 can contribute to cognitive deficits.
Developing approaches to positively modulate mGlu3 receptor function represents
an encouraging new avenue for treating cognitive disruption in schizophrenia and
other psychiatric diseases.




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