What should we target to treat depression? From receptors and circuits to remission. (360G-Wellcome-333962_Z_25_Z)

Major depressive disorder (MDD) is a debilitating condition with most existing treatments being slow-acting or ineffective for many patients or depressive symptoms. Ketamine has shown promise as a fast-acting antidepressant that alleviates symptoms within hours; however, its effects are short-lived and it poses risks of abuse, highlighting the need for safer, more precise and longer-lasting treatments. Using an established chronic stress model, which elicits depression-related phenotypes in rodents, my recent research shows that ketamine’s antidepressant action begins with the inhibition of somatostatin-expressing (Sst+) interneurons in the medial prefrontal cortex (mPFC)—identifying this heterogenous neuronal population as key initiators of antidepressant effects. Here, I will delineate the Sst+ subtypes initiating antidepressant effects, to determine the precise circuit mechanisms induced by antidepressants. Next, I will uncover how different Sst+ subtypes influence distinct depression-related behaviours to identify precise ways to alleviate specific symptoms by targeting these subtypes. I will also investigate how ketamine restores cell-type-specific, stress-induced changes, with the goal of modulating these pathways to prolong antidepressant outcomes. Ultimately, I aim to deepen our understanding of mPFC-mediated antidepressant mechanisms and the pathophysiology underlying depressive symptoms to support the development of novel, multi-target treatments with lasting effects for MDD patients.