Downregulation Of Kcnmb4 Expression And Changes In Bk Channel Subtype In Hippocampal Granule Neurons Following Seizure Activity
PLOS ONE(2017)
摘要
A major challenge is to understand maladaptive changes in ion channels that sets neurons on a course towards epilepsy development. Voltage-and calcium-activated K+ (BK) channels contribute to early spike timing in neurons, and studies indicate that the BK channel plays a pathological role in increasing excitability early after a seizure. Here, we have investigated changes in BK channels and their accessory beta 4 subunit (KCNMB4) in dentate gyrus (DG) granule neurons of the hippocampus, key neurons that regulate excitability of the hippocampus circuit. Two days after pilocarpine-induced seizures, we found that the predominant effect is a downregulation of the beta 4 accessory subunit mRNA. Consistent with reduced expression, single channel recording and pharmacology indicate a switch in the subtype of channels expressed; from iberiotoxin-resistant, type II BK channels (BK alpha/beta 4) that have higher channel open probability and slow gating, to iberiotoxin-sensitive type I channels (BK a alone) with low open probability and faster gating. The switch to a majority of type I channel expression following seizure activity is correlated with a loss of BK channel function on spike threshold while maintaining the channel's contribution to increased early spike frequency. Using heterozygous beta 4 knockout mice, we find reduced expression is sufficient to increase seizure sensitivity. We conclude that seizure-induced downregulation of KCNMB4 is an activity dependent mechanism that increases the excitability of DG neurons. These novel findings indicate that BK channel subtypes are not only defined by cell-specific expression, but can also be plastic depending on the recent history of neuronal excitability.
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关键词
kcnmb4 expression,hippocampal granule neurons,bk channel subtype,granule neurons,seizure
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