Sex Differences in the Temporal Neuromolecular and Synaptogenic Effects of the Rapid-acting Antidepressant Drug Ketamine in the Mouse Brain

Preclinical evidence suggests that ketamine's rapid and sustained antidepressant actions are due to the induction of synaptogenesis in the medial prefrontal cortex (mPFC) and the hippocampus (HIPP), two brain regions implicated in the pathophysiology of major depression. However, research on the neurobiological effects of ketamine has focused almost exclusively on males. Findings from our group and others indicate that female rodents are more reactive to ketamine's antidepressant effects, since they respond to lower doses in antidepressant-predictive behavioral models. The sex-dependent mechanisms that mediate the antidepressant effects of ketamine in the female brain are elusive. Herein, we assessed the neurobiological effects of a single ketamine dose (10 mg/kg; previously shown to induce rapid and sustained antidepressant-like effects in mice of both sexes), on glutamate release in the mPFC, as well as on the expression of synaptic plasticity markers, and spine density in the mPFC and the HIPP of C57BL/6J mice. Our data revealed that ketamine induced a sex-specific "glutamate burst" in the male mPFC. Ketamine activated the mammalian target of rapamycin complex 1 (mTORC1) pathway in prefrontocortical synaptoneurosomes, and enhanced spine formation in the male mPFC and HIPP. In females, ketamine induced a sustained increase in hippocampal spine density. Overall, these data exposed a sharp sex difference in the synaptogenic response to ketamine in stress-naïve mice, and further suggest that the mPFC may play a more important role in mediating the antidepressant effects of the drug in males, while the HIPP may be more important for females.