Abstracts

Rationale: Epileptogenesis develops during recurring hyperexcitability in the brain and results in increased susceptibility to seizures. Voltage-gated KCNQ2/3 K+ channels (M-channels) limit excitability by modulating resting membrane potential and spike frequency adaptation. Genetic loss-of-function mutations in KCNQ2/3 result in benign familial neonatal seizures. However, little is known about M-channel organization and function subsequent to epileptic seizures. We sought to further investigate the role of M-channels in modulation of excitability in the hippocampus. We hypothesized the upregulation of M-channel expression after chemoconvlsant seizures would confer protection to further insult when targeted with M-channel openers. In addition, we hypothesized that loss-of-function of M-channels specific to DG granule cells would result in neuronal hyperexcitability leading to increased seizure susceptibility and facilitation of epileptogenesis. Methods: We used KCNQ2 and KCNQ3 conditional knockout mice to investigate M-channel loss of function specific to the DG. Transgenic floxed mice for KCNQ2 and/or KCNQ3 were crossed with Cre-POMC hemizygous mice to yield conditional knockout of M-channels in new-born granule cells. We studied whole-cell patch-clamp electrophysiology properties of granule cells in comparison to litter mate controls. M-channel DG knockout mice were investigated for spontaneous seizures, severity, and seizure susceptibility using chemoconvulsant models in comparison with wildtype controls. Results: Granule cell hemizygosity for KCNQ2/3 and knockout of KCNQ2 produced increased seizure susceptibility in adult animals. Granule cells without KCNQ2 exhibited altered passive and active discharge properties indicative of hyperexcitability. For each of the KCNQ2 or KCNQ3 knockouts, we analyzed the compensational plasticity in the partnering KCNQ subunit of M-channels. We also observed compensational changes to GABAA receptors in KCNQ knockout mice. Conclusions: We have described an important adaptational role of KCNQ2/3 M-type channels in the dentate gyrus during hyperexcitability. M-channels have an functional role in the hippocampus to limit excitatory inputs through the DG. These findings may suggest that KCNQ channels strongly regulate DG granule cell excitability and in turn modulate the DG gate-keeping function for the rest of the hippocampus in protection from epileptiform events. Funding: This work was supported by UTHSCSA School of Medicine Award (to MSS) and an NIH instutional training fellowship T32 HL007446 (to CMC)