Major depressive disorder (MDD) is a psychiatric disorder with a lifetime prevalence of ~15% and is the leading cause of disability worldwide¹. The societal burden of MDD is immense, causing profound personal suffering and economic loss, which has recently been intensified by the Covid-19 pandemic². The most effective treatments for MDD, a class of antidepressants called the selective serotonin reuptake inhibitors (SSRIs), are successful in achieving remission, but only in ~40% of patients³. Despite being in use for over 50 years, it remains unknown how SSRIs modulate neural circuit function in patients that achieve remission and where these mechanisms are disrupted in those that do not. Thus, a fundamental question remains: What are cellular and molecular mechanisms that mediate antidepressant response and resistance? Defining the answers to this question could provide fundamental insights into the pathophysiology of MDD and uncover novel substrates for future precision medicine approaches.