Ablation of cerebellar Purkinje cells enhances seizure susceptibility and promotes kindling

Objective Epilepsy is a common neurological disorder characterized by recurrent seizures, often resulting from an imbalance between neuronal excitation and inhibition. Loss of cerebellar Purkinje cells (PCs) has been observed in some patients with chronic epilepsy; however, whether PC loss can initiate seizures or exacerbate seizure severity remains unclear. Methods We established a mouse model of selective PC ablation in adulthood using the diphtheria toxin (DT)/DT receptor (DTR) system. Seizure susceptibility (epileptiform discharges, Racine score, and network activation) was assessed thoroughly in two distinct seizure models: the pentylenetetrazol (P‐uced acute seizure model and the hippocampal kindling model. Furthermore, in vivo electrophysiology recordings in the deep cerebellar nuclei (DCN) were utilized to explore the single‐unit firing characteristics following PC ablation. Results One month after intraperitoneal (i.p.) DT injection, PC ablation was successfully induced in adult Pcp2‐DTR mice. No spontaneous seizures were observed in mice with PC ablation during 48‐h wireless electroencephalography/electromyography (EEG/EMG) monitoring. However, PC ablation significantly increased seizure susceptibility in the PTZ‐induced acute seizure model and accelerated the kindling process in the hippocampal kindling model. Although baseline DCN firing remained unchanged, these mice displayed a distinct post‐ictal DCN electrophysiological signature: significantly enhanced delta/theta power compared to controls, and a decrease in neuronal firing frequency relative to their own baseline, with firing regularity preserved. Significance Together, these findings suggest that PC ablation contributes to heightened seizure susceptibility and seizure severity, highlighting a modulatory role of cerebellar circuits in epilepsy.