Activating mGlu3 Metabotropic Glutamate Receptors Rescues Schizophrenia-like Cognitive Deficits Through Metaplastic Adaptations Within the Hippocampus.

Polymorphisms in GRM3 , the gene encoding the mGlu 3 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 3 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 mGlu 3 receptor expression in specific neuronal subpopulations. mGlu 3 receptor activation enhanced trace fear conditioning and reversed deficits induced by subchronic phencyclidine. Mechanistic studies revealed that mGlu 3 receptor activation induced metaplastic changes, biasing afferent stimulation to induce long-term potentiation through an mGlu 5 receptor–dependent, endocannabinoid-mediated, disinhibitory mechanism. Selective genetic deletion of either mGlu 3 or mGlu 5 from hippocampal pyramidal cells eliminated effects of mGlu 3 activation, revealing a novel mechanism by which mGlu 3 and mGlu 5 interact to enhance cognitive function. These data demonstrate that activation of mGlu 3 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 3 receptor function represents an encouraging new avenue for treating cognitive disruption in schizophrenia and other psychiatric diseases. [ABSTRACT FROM AUTHOR]