Activating mGlu₃ Metabotropic Glutamate Receptors Rescues Schizophrenia-like Cognitive Deficits Through Metaplastic...

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.