Impacted Spike Frequency Adaptation Associated with Reduction of KCNQ2/3 Promotes Seizure Activity in Temporal Lobe Epilepsy

Abstract

Although numerous epilepsy-related genes have been identified by unbiased genome-wide screening based on samples from both animal models and patients, the druggable targets for temporal lobe epilepsy (TLE) are still limited. Meanwhile, a large number of candidate genes that might promote or inhibit seizure activities are waiting for further validation. In this study, we first analyzed two public databases and determined the significant down-regulations of two M-type potassium channel genes (KCNQ2/3) expressions in hippocampus samples from TLE patients. Then we reproduced the similar pathological changes in the pilocarpine mouse model of TLE and further detected the decrease of spike frequency adaptation driven by impacted M-currents on dentate gyrus granule neurons. Finally, we employed a small-scale simulation of dentate gyrus network to investigate potential functional consequences of disrupted neuronal excitability. We demonstrated that the impacted spike frequency adaptation of granule cells facilitated the epileptiform activity among the entire network, including prolonged seizure duration and reduced interictal intervals. Our results identify a new mechanism contributing to ictogenesis in TLE and suggest a novel target for the anti-epileptic drug discovery.