Individual differences in the chronic stress-induced depression-like behavior are mediated by the expression of Kcnj2 gene in the lateral septum

It has been demonstrated that chronic unpredictable mild stress (CUMS) induces depression-like behaviors in mice. Notably, there are differences among individuals in the extent to which these behaviors are exhibited, similar to humans. In this study, we focused on individual differences and examined which brain areas have differences in neuronal excitability, and which genes are differentially expressed between stress-susceptible mice with depression-like behaviors and stress-resilient mice without depression-like behaviors (Stress-S and -R). After 8 weeks of CUMS, the number of c-Fos positive cells was fewer in Stress-R mice compared to Stress-S mice only in the cingulate cortex and lateral septum. RNA-seq analysis revealed an upregulation of Kcnj2 mRNA, the gene for the inward-rectifying potassium channel (Kir2.1), in the lateral septum of Stress-R mice, without affecting the expression of other potassium channels. The expression of genes related to adult neurogenesis, neuroinflammation, hypothalamic-pituitary-adrenal axis, BDNF, and monoamine hypotheses were similar between Stress-S and -R mice. Intra-septal injections of Kir2.1 activators, flecainide and GPV0057, showed antidepressant effects in the tail-suspension test. These findings suggest that Stress-R behavior is the result of the upregulation of Kir2.1 and decreased neuronal excitability in the lateral septum. They also suggest the uniqueness of this model and the potential to reveal new mechanisms.