Frontal cortex genetic ablation of metabotropic glutamate receptor subtype 3 (mGlu3) impairs postsynaptic plasticity and modulates affective behaviors

Clinical and translational studies suggest that prefrontal cortex (PFC) dysregulation is a hallmark feature of several affective disorders. Thus, investigating the mechanisms involved in the regulation of PFC function and synaptic plasticity could aid in developing new medications. In recent years, the mGlu(2) and mGlu(3) subtypes of metabotropic glutamate (mGlu) receptors have emerged as exciting potential targets for the treatment of affective disorders, as mGlu(2/3) antagonists exert antidepressant-like effects across many rodent models. Several recent studies suggest that presynaptic mGlu(2) receptors may contribute to these effects by regulating excitatory transmission at synapses from the thalamus to the PFC. Interestingly, we found that mGlu(3) receptors also inhibit excitatory drive to the PFC but act by inducing long-term depression (LTD) at amygdala-PFC synapses. It remains unclear, however, whether blockade of presynaptic, postsynaptic, or glial mGlu(3) receptors contribute to long-term effects on PFC circuit function and antidepressant-like effects of mGlu(2/3) antagonists. To address these outstanding questions, we leveraged transgenic Grm3(fl/fl) mice and viral-mediated gene transfer to genetically ablate mGlu(3) receptors from pyramidal cells in the frontal cortex of adult mice of all sexes. Consistent with a role for mGlu(3) in PFC pyramidal cells, mGlu(3)-dependent amygdala-cortical LTD was eliminated following mGlu(3) receptor knockdown. Furthermore, knockdown mice displayed a modest, task-specific anxiolytic phenotype and decreased passive coping behaviors. These studies reveal that postsynaptic mGlu(3) receptors are critical for mGlu(3)-dependent LTD and provide convergent genetic evidence suggesting that modulating cortical mGlu(3) receptors may provide a promising new approach for the treatment of mood disorders.

Automated summary

Prefrontal cortex dysregulation is a hallmark feature of several affective disorders, and mGlu(2/3) receptors may serve as potential targets for their treatment. Studies suggest that mGlu(3) receptors play a critical role in PFC pyramidal cells, and their knockdown could lead to anxiolytic effects and decreased passive coping behaviors.