Abstract
Exposure to stress is recognized to be a triggering factor in several mood disorders, including depression and anxiety. There is very little understanding of why female subjects have a significantly higher risk for these conditions than males. Recent findings in male rodents indicated that prophylactic ketamine can prevent the development of a stress-induced depressive-like phenotype, providing a pharmacological tool to study the mechanisms underlying stress resilience. Unfortunately, none of these studies incorporated female subjects, nor did they provide a mechanistic understanding of the effects of ketamine on stress resilience. Our previous work identified the prefrontal glutamatergic and parvalbumin (PV) systems as potential molecular mechanisms underlying sex differences in susceptibility to stress-induced emotional deregulations. To further address this point, we treated male and female mice with a single dose of ketamine before exposure to a chronic stress paradigm to determine whether stress-resilience induced by a pre-exposure to ketamine is similar in males and females and whether modulation of the prefrontal glutamatergic and PV systems by ketamine is associated with these behavioral effects. Ketamine prevented chronic stress-induced changes in behaviors in males, which was associated with a reduction in expression of PV and the NMDA receptor NR1 subunit. Ketamine did not protect females against the effects of chronic stress and did not change significantly prefrontal gene expression. Our data highlight fundamental sex differences in the sustained effects of ketamine. They also further implicate prefrontal glutamatergic transmission and PV in resilience to chronic stress.
Highlights
Depression and anxiety are mood disorders characterized by an inherent sex bias
Based on the known influence of ketamine on glutamatergic and GABAergic transmission (Gerhard et al, 2016, 2020), and on our previous work showing that Unpredictable Chronic Mild Stress (UCMS) caused changes in PV expression in the prefrontal cortex (PFC) of male and female mice that correlated with changes in emotional behavior (Shepard et al, 2016), we hypothesize that prophylactic ketamine provides resilience to stress-induced changes in emotional deregulations via alterations in excitation and inhibition in the PFC
The RT-qPCR analysis revealed that males experienced more changes in the expression of prefrontal markers of NMDA receptors and PV-dependent GABAergic transmission. mRNA levels of NR1 and PV were significantly reduced in the PFC of males 7 days post-ketamine (Figures 2A,C; NR1: t(9) = 2.35, p = 0.04; PV: t(8) = 2.30, p = 0.05)
Summary
Depression and anxiety are mood disorders characterized by an inherent sex bias. are women at increased risk for developing these conditions (Kendler, 1998; Kessler, 2003), but they often display more severe symptoms and higher prevalence of experiencing anxiety as a comorbid symptom to depression (de Graaf et al, 2002; Schoevers et al, 2003). Other neural circuits and molecular mechanisms that are known to be major contributors to mood disorders have been largely ignored, limiting our understanding of sex-specific vulnerability to stress-related mood disorders Both clinical and preclinical studies highlighted deregulations of the prefrontal cortex (PFC) in mood disorders (Baxter et al, 1989; Mayberg et al, 2005; Covington et al, 2010). Reduced activity of the PFC is a hallmark of anxiety disorders and depression (Martinot et al, 1990; Shin et al, 2001; Thompson et al, 2015) This brain region is of particular importance since, in preclinical studies, the PFC of females was found to be especially sensitive to stress (Garrett and Wellman, 2009; Shansky et al, 2010)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
