Cerebellar Kv2.1 downregulation, cytoarchitectural alterations, and persistent motor impairments following subchronic...

Dysfunction of the cerebellum is increasingly recognised as a contributor to schizophrenia. As one of the most ubiquitous voltage-gated potassium channels in the brain, the expression and function of Kv2.1 remains underexplored in the cerebellum, and its potential involvement in cerebellar pathophysiology in schizophrenia is unknown. Here, we characterised the expression pattern of Kv2.1 in the cerebellar cortex and examined its changes, along with cerebellar cytoarchitecture, in a subchronic phencyclidine male mouse model of schizophrenia. Behavioural performance was assessed throughout phencyclidine treatment and during a one-week washout using the horizontal bar, vertical pole, and beam walk tests, focusing on indices of fine motor coordination and balance. Significant alterations emerged during treatment. Notably, four parameters, the number of swings on the bar, time to complete the T-turn, time to cross the beam, and number of foot slips, remained impaired after washout, indicating persistent deficits in motor coordination and balance. Fluorescence imaging showed Kv2.1 expression on the soma, proximal dendrite, and axon initial segment of Purkinje cells, and in granule cell somata and dendrites. After washout, Western blot revealed reduced cerebellar Kv2.1 levels, corroborated by fluorescence analyses showing downregulation in both Purkinje and granule cells. In addition, cytoarchitectural changes were detected, including globally reduced Purkinje cell soma size and a hemisphere-specific decrease in NeuN-positive granule cell density. Overall, this study provides a descriptive account of cerebellar cytoarchitectural and Kv2.1 expression changes, alongside persistent motor impairments, associated with subchronic phencyclidine exposure, warranting future studies on mechanistic links between cerebellar neuropathology and behavioural performance.