Investigating electrophysiological changes and Glycogen Synthase Kinase-3 activity in the medial prefrontal cortex in a mouse model of depression

Major Depressive Disorder is characterized by a significant reduction in medial prefrontal cortex (mPFC) activity, yet the intrinsic cellular mechanisms driving this dysfunction remain poorly understood. While structural deficits like spine loss are well-documented, this thesis investigates whether alterations in the firing properties of layer 2/3 pyramidal neurons, the primary integration hub of the mPFC, are the cause of this hypoactivity. Using the chronic social defeat stress (CSDS) model, we identified neuronal hypoexcitability in susceptible mice. This was characterized by a reduced firing rate and enhanced frequency adaptation, driven by a significantly higher afterhyperpolarization (AHP) amplitude. Interestingly, these changes were not caused by a transcriptional upregulation of the potassium K+ channels that typically control these properties. Instead, we investigated the role of Glycogen Synthase Kinase 3 (GSK3), a kinase hyperactive in both human patients and our susceptible mice. To determine if GSK3 hyperactivity was the cause of this reduced excitability, we utilized a genetic GSK3 knock-in model. Surprisingly, constitutively active GSK3 produced the opposite effect, promoting intrinsic hyperexcitability. These results suggest that while GSK3 is hyperactive in the depressed brain, it is not the driver of hypoexcitability; rather, it may represent a failed compensatory mechanism attempting to restore normal neuronal output during chronic stress. By identifying intrinsic hypoexcitability as a hallmark of depression, this work shifts the focus from simple neurotransmitter deficits to the active conductances of the mPFC. These findings suggest that future therapeutic strategies should aim to restore prefrontal firing to reengage emotional regulation.