BK channel beta4 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 beta4 subunits serve as key regulators of intrinsic firing properties that contribute to the low-pass filtering function of dentate granule cells. Notably, a critical beta4 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 beta4 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, beta4 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.
Brenner
Robert
R
Department of Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78229, USA.
Chen
Qing H
QH
Vilaythong
Alex
A
Toney
Glenn M
GM
Noebels
Jeffrey L
JL
Aldrich
Richard W
RW
D000200:Action Potentials / Q000235:genetics*; D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D002450:Cell Communication / Q000235:genetics; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D018891:Dentate Gyrus / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D015640:Ion Channel Gating / Q000235:genetics; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000235:genetics*; D009434:Neural Pathways / Q000378:metabolism* / Q000503:physiopathology; D009924:Organ Culture Techniques; D021122:Protein Subunits / Q000235:genetics; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics
D051036:Large-Conductance Calcium-Activated Potassium Channels; D021122:Protein Subunits; D051640:Small-Conductance Calcium-Activated Potassium Channels