Knockout of α-Synuclein Is Associated with Depression-like Behaviors by Altered Excitability of Medial Prefrontal Cortex Neurons in Mice

To investigate the neural circuit mechanisms linking the physiological loss of α-synuclein (α-syn) function to depressive-like states, we explored whether constitutive α-syn depletion disrupts the excitation and inhibition balance within the medial prefrontal cortex. We integrated comprehensive behavioral paradigms, whole-cell patch-clamp electrophysiology, and targeted chemogenetics within an α-syn knockout mouse model. Behavioral profiling revealed that α-syn deficiency was accompanied by basal psychomotor hyperactivity and profound stress-coping deficits. Cellular electrophysiology in the medial prefrontal cortex demonstrated a significantly enhanced intrinsic excitability across both GABAergic and glutamatergic populations. Furthermore, targeted chemogenetic suppression of GAD67-positive interneurons partially alleviated the depressive-like phenotype without confounding baseline locomotion. In summary, the physiological depletion of endogenous α-syn is associated with altered stress-coping behaviors and increased mPFC neuronal excitability. Chemogenetic suppression of mPFC GAD67-positive interneurons partially reduces immobility in SYN-KO mice, implicating prefrontal inhibitory circuit dysregulation in these behavioral alterations. These findings underscore the importance of α-syn homeostasis in modulating cortical microcircuits and provide novel insights into the early non-motor manifestations of synucleinopathies.