HYPERACTIVE GSK3 SIGNALING FAILS TO PRESERVE MPFC NEURONAL EXCITABILITY IN MICE SUSCEPTIBLE TO CHRONIC SOCIAL DEFEAT STRESS

Chronic stress compromises the function of the medial prefrontal cortex (mPFC), a key hub for emotional regulation. While cortical hypoactivity is a hallmark of depression, the cellular and molecular mechanisms driving this dysfunction remain debated. We combined the Chronic Social Defeat Stress (CSDS) model in mice with ex vivo whole-cell patch-clamp recordings to characterize layer 2/3 pyramidal neurons of the mPFC. Susceptible mice exhibited intrinsic hypoexcitability, driven by enhanced frequency adaptation and increased afterhyperpolarization (AHP) amplitude. Transcriptional analysis of relevant K+ channels ruled out gene upregulation as the cause of this altered excitability, pointing toward post-translational regulation. Consistent with this, we identified hyperactivation of Glycogen Synthase Kinase-3 (GSK3), a modulator of ion channel opening and trafficking. To test causality, we recorded from GSK3 knock-in (KI) mice expressing constitutively active GSK3. Surprisingly, GSK3 KI neurons did not recapitulate the stress phenotype but exhibited the opposite: intrinsic hyperexcitability. These findings reveal a dissociation between the kinase activity and the pathological phenotype. We propose that GSK3 hyperactivation observed after chronic stress is not the driver of reduced excitability but represents a homeostatic mechanism that attempts to counteract the negative impact of social stress by maintaining mPFC excitability. This identifies GSK3 signaling as an adaptive response to stress, offering a new perspective on cortical dysfunction in depression.