KV3.1 MODULATION RESTORES FAST-SPIKING IN PARVALBUMIN INTERNEURONS DESPITE REDUCED EXCITATORY SYNAPTIC INPUT IN CHRONIC EPILEPSY

Parvalbumin-positive interneurons (PV-INs) are essential for maintaining hippocampal excitatory–inhibitory balance, a key requirement for learning and memory. Although PV-IN dysfunction is a hallmark of epilepsy, the mechanisms underlying its failure remain poorly defined. Using PV-Cre:Ai9 mice, we induced chronic epilepsy via pentylenetetrazole (PTZ) kindling (35 mg/kg, i.p., every 48 h, 8–12 injections) until generalized seizures developed. Epileptic mice displayed a ~10% reduction in novel object exploration in the object location memory (OLM) task, indicating a spatial memory deficit independent of anxiety-like behavior (Open Field test). To identify the cellular correlates of these behavioral impairments, we performed whole-cell recordings from CA1 PV-INs. Despite having depolarized resting membrane potentials, PV-INs from epileptic mice showed reduced firing frequency, slowed action potential repolarization, and altered afterhyperpolarizations -electrophysiological signatures consistent with Kv3.1 channel dysfunction. At the synaptic level, excitatory drive onto PV-INs was reduced, as shown by a lower frequency of spontaneous excitatory postsynaptic currents and diminished input–output relationships of evoked excitatory responses. Importantly, bath application of the Kv3.1 positive modulator AUT1 (5 µM) restored PV-IN firing frequency in epileptic mice to control levels. The present findings identify impaired Kv3.1-dependent intrinsic excitability as a key mechanism of PV-IN dysfunction after epilepsy onset. Enhancing Kv3.1 activity has been demonstrated to be an effective strategy for restoring fast-spiking capability, thus underscoring the potential of Kv3.1 channels as a promising therapeutic target for the restoration of interneuron function and the stabilization of hippocampal network dynamics.