Delving deep inside the neural circuitry of "depressed" mice, researchers have revealed how ketamine works in cells to achieve its fast-acting antidepressant effect. The drug restores dendritic spine formation in the prefrontal cortex, the study shows; the work also reveals the critical role for healthy dendritic spines in maintaining long-term antidepressant effects. "...this study brings crucial results for the development of innovative strategies to treat patients affected by treatment-resistant depression," writes Anna Beyeler in a related Perspective. Major depression affects nearly 20% of the U.S. population, many of whom experience a relapse in symptoms following clinical treatment. Despite the prevalence of the mental illness, the neural circuitry that drives the ebb and flow of depressive episodes is not well understood, resulting in limited treatment options. Recent studies have demonstrated the promising antidepressant properties of ketamine; in March 2019, the American Food and Drug Association (FDA) approved a ketamine-derived nasal spray for the treatment of treatment-resistant depression, even as the drug's underlying mechanism of action remains unknown, and its effects short-lived. Rachel Moda-Sava and colleagues sought to uncover it using a mouse model of depression. Using recently developed technologies capable of imaging dendritic spines, tiny structures that line the dendrites of neurons and help form synapses, thus facilitating the electrical activity that flashes between them, Moda-Sava et al. found that depression-related behavior in mice was associated with the elimination of dendritic spines on neurons in the prefrontal cortex. When given an antidepressant-dose of ketamine, the spines were restored to some extent, however, and the behavior effects were reversed, likely because of the way communication between synapses of prefrontal microcircuits was able to continue. The authors suggest that interventions designed to enhance the survival of restored synapses may be helpful in sustaining - for the long-term - the promising antidepressant effects of ketamine.