Depression in mice causes decreased neuronal excitability and enhanced frequency adaptation in medial prefrontal cortex pyramidal neurons

Depression is a major problem of contemporary society, with limited treatment efficacy due to incomplete understanding of cellular and molecular mechanisms. The medial prefrontal cortex (mPFC) is involved in stress response and depression, but the neuronal mechanisms are still debated. We induced a depressive-like behavior in mice by chronic social defeat stress. mPFC neuronal activity was recorded in cortical slices of susceptible mice that developed social avoidance, in resilient and in controls not subjected to the stress protocol. In susceptible mice, pyramidal neurons of mPFC layer 2/3 displayed reduced excitability with preserved passive membrane properties. Analysis of evoked firing revealed that the decreased excitability was due to a pronounced frequency adaptation. The mechanisms were investigated by analyzing single action potentials. We found a higher voltage threshold and an enhanced afterhyperpolarization, which are considered as determinants of hypo-excitability. Increased frequency adaptation impairs the ability to sustain firing during afferent excitatory inputs, thus disrupting the synchronization and stability of the mPFC network activity. Since mPFC layer 2/3 is connected to other brain regions involved in emotional regulation and stress responses, our results suggest that its neuronal dysfunction can be an important mechanism of mood alteration and depressed behavior.