The medial prefrontal cortex is a sex-specific mediator of ketamine’s antidepressant action

Diagnosis of Major Depressive Disorder (MDD) has steadily been increasing in recent years and by 2030 this neuropsychiatric disease is projected to be the leading cause of disease burden world-wide. While MDD is more prevalent than ever before, new treatment options are being explored to provide rapid and long-lasting relief. One of the most promising candidates is the non-competitive N-methyl-D-aspartate receptor antagonist ketamine. This drug, in low doses, has been shown to alleviate symptoms of depression within hours in both animal models and treatment-resistant depressed patients. Despite this revolutionary finding, research focusing on the effects of ketamine has been predominantly conducted in males. What’s more, recent studies have identified a sex-specific antidepressant response to ketamine making the need for further investigation imperative to ketamine’s future role as an effective treatment option for both males and females. In this study, the role of the medial prefrontal cortex (mPFC) in mediating ketamine’s antidepressant response was assessed in stress-naïve male and female C57BL/6J mice. It was discovered that ketamine induced male-specific neuromolecular alterations in the mPFC that may underlie the drug’s therapeutic effects; these same alterations in protein expression and synaptic spine density were not present in females. Taken together, the data supports that the mPFC may be more important in regulating the male antidepressant response to ketamine whereas other brain regions may play a greater role in orchestrating ketamine’s beneficial effects in females