期刊
NATURE NEUROSCIENCE
卷 8, 期 12, 页码 1752-1759出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nn1573
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资金
- NHLBI NIH HHS [R01 HL071645] Funding Source: Medline
- NICHD NIH HHS [HD24064] Funding Source: Medline
- NINDS NIH HHS [NS29709] Funding Source: Medline
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.
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