Metabotropic glutamate receptor subtype 3 gates acute stress-induced dysregulation of amygdalo-cortical function

Stress can precipitate or worsen symptoms of many psychiatric disorders by dysregulating glutamatergic function within the prefrontal cortex (PFC). Previous studies suggest that antagonists of group II metabotropic glutamate (mGlu) receptors (mGlu₂ and mGlu₃) reduce stress-induced anhedonia through actions in the PFC, but the mechanisms by which these receptors act are not known. We now report that activation of mGlu₃ induces long-term depression (LTD) of excitatory transmission in the PFC at inputs from the basolateral amygdala. Our data suggest mGlu₃-LTD is mediated by postsynaptic AMPAR internalization in PFC pyramidal cells, and we observed a profound impairment in mGlu₃-LTD following a single, 20-min restraint stress exposure. Finally, blocking mGlu₃ activation in vivo prevented the stress-induced maladaptive changes to amydalo-cortical physiology and motivated behavior. These data demonstrate that mGlu₃ mediates stress-induced physiological and behavioral impairments and further support the potential for mGlu₃ modulation as a treatment for stress-related psychiatric disorders.