Metabotropic Glutamate Receptor 5 in Amygdala Target Neurons Regulates Susceptibility to Chronic Social Stress

Abstract

Background: Metabotropic glutamate receptor 5 (mGluR5) has been implicated in stress-related psychiatric disorders, particularly major depressive disorder. Although growing evidence supports the proresilient role of mGluR5 in corticolimbic circuitry in the depressive-like behaviors following chronic stress exposure, the underlying neural mechanisms, including circuits and molecules, remain unknown. Methods: We measured the c-Fos expression and probability of neurotransmitter release in and from basolateral amygdala (BLA) neurons projecting to the medial prefrontal cortex (mPFC) and to the ventral hippocampus (vHPC) after chronic social defeat stress. The role of BLA projections in depressive-like behaviors was assessed using optogenetic manipulations, and the underlying molecular mechanisms of mGluR5 and downstream signaling were investigated by Western blotting, viral-mediated gene transfer, and pharmacological manipulations. Results: Chronic social defeat stress disrupted neural activity and glutamatergic transmission in both BLA projections. Optogenetic activation of BLA projections reversed the detrimental effects of chronic social defeat stress on depressive-like behaviors and mGluR5 expression in the mPFC and vHPC. Conversely, inhibition of BLA projections of mice undergoing subthreshold social defeat stress induced a susceptible phenotype and mGluR5 reduction. These two BLA circuits appeared to act in an independent way. We demonstrate that mGluR5 overexpression in the mPFC or vHPC was proresilient while the mGluR5 knockdown was prosusceptible and that the proresilient effects of mGluR5 are mediated through distinctive downstream signaling pathways in the mPFC and vHPC. Conclusions: These findings identify mGluR5 in the mPFC and vHPC that receive BLA inputs as a critical mediator of stress resilience, highlighting circuit-specific signaling for depressive-like behaviors. © 2022 Society of Biological Psychiatry