Activating mGlu Metabotropic Glutamate Receptors Rescues Schizophrenia-like Cognitive Deficits Through Metaplastic Adaptations Within the Hippocampus.

Background: Polymorphisms in GRM3, the gene encoding the mGlu 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 mGlu receptors regulate synaptic plasticity and cognition.

Methods: 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 mGlu receptor expression in specific neuronal subpopulations.

Results: mGlu receptor activation enhanced trace fear conditioning and reversed deficits induced by subchronic phencyclidine. Mechanistic studies revealed that mGlu receptor activation induced metaplastic changes, biasing afferent stimulation to induce long-term potentiation through an mGlu receptor-dependent, endocannabinoid-mediated, disinhibitory mechanism. Selective genetic deletion of either mGlu or mGlu from hippocampal pyramidal cells eliminated effects of mGlu activation, revealing a novel mechanism by which mGlu and mGlu interact to enhance cognitive function.

Conclusions: These data demonstrate that activation of mGlu 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 mGlu receptor function represents an encouraging new avenue for treating cognitive disruption in schizophrenia and other psychiatric diseases.