BK channel β4 subunit reduces dentate gyrus excitability and protects against temporal lobe seizures

Synaptic inhibition within the hippocampus dentate gyrus serves a 'low-pass filtering' function that protects against hyperexcitability that leads to temporal lobe seizures. Here we demonstrate that calcium-activated potassium (BK) channel accessory beta 4 subunits serve as key regulators of intrinsic firing properties that contribute to the low-pass filtering function of dentate granule cells. Notably, a critical b4 subunit function is to preclude BK channels from contributing to membrane repolarization and thereby broaden action potentials. Longer-duration action potentials secondarily recruit SK channels, leading to greater spike frequency adaptation and reduced firing rates. In contrast, granule cells from beta 4 knockout mice show a gain-of-function for BK channels that sharpens action potentials and supports higher firing rates. Consistent with breakdown of the dentate filter, beta 4 knockouts show distinctive seizures emanating from the temporal cortex, demonstrating a unique nonsynaptic mechanism for gate control of hippocampal synchronization leading to temporal lobe epilepsy.