Abstract

Psychiatric diseases are driven by dysregulation at the molecular and synaptic levels that lead to maladaptive changes in discrete neural circuits that drive behavioral symptoms. While therapeutic approaches have typically been based on the serendipitous identification of symptom-alleviating compounds, a deeper understanding of the underlying mechanisms of both the pathophysiology and treatment of psychiatric disease has great promise to guide the development of improved treatments. Here we focus on deciphering the action of the novel antidepressant ketamine as a means of identifying new G protein-coupled receptor (GPCR) antidepressant targets. We first find that ketamine exerts its behavioral effects through agonism of mu-opioid receptors which are enriched on the axons of SST interneurons in the medial prefrontal cortex. mPFC SST interneurons both drive the rapid initiation of ketamine’s circuit and behavioral effects and serve as key mediators of the effects of chronic unpredictable stress via axonal hypertrophy which leads to excessive mPFC inhibition. Driven by these mechanistic findings, we use cell type-targeted RNA sequencing to identify SST -enriched GPC Rs which can drive antidepressant responses upon agonism or antagonism. Most notably, synergistic targeting of multiple SST enriched GPC Rs enables antidepressant responses with enhanced efficacy and reduced side effect profiles compared to ketamine. Together this study reveals new mechanistic insights with promise to improve antidepressant strategies and reveals a general approach to identifying new therapeutic GPCR targets for brain disorders.