Whitmire Luke E, Ling Ling, Bugay Vladslav, Carver Chase M, Timilsina Santosh, Chuang Hui-Hsiu, Jaffe David B, Shapiro Mark S, Cavazos Jose E, Brenner Robert
Department of Cell and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
Department of Biology, University of Texas at San Antonio, San Antonio, Texas, United States of America.
PLoS One. 2017 Nov 16;12(11):e0188064. doi: 10.1371/journal.pone.0188064. eCollection 2017.
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 β4 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 β4 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 α/β4) that have higher channel open probability and slow gating, to iberiotoxin-sensitive type I channels (BK α 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 β4 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.
一个主要挑战是了解离子通道中的适应不良变化，这些变化使神经元走上癫痫发展的道路。电压门控和钙激活的钾离子（BK）通道有助于神经元的早期放电时间，并且研究表明BK通道在癫痫发作后早期增加兴奋性方面起病理作用。在这里，我们研究了海马齿状回（DG）颗粒神经元中BK通道及其辅助β4亚基（KCNMB4）的变化，这些颗粒神经元是调节海马回路兴奋性的关键神经元。毛果芸香碱诱导癫痫发作两天后，我们发现主要影响是β4辅助亚基mRNA的下调。与表达减少一致，单通道记录和药理学表明所表达通道的亚型发生了转换；从具有较高通道开放概率和缓慢门控的抗iberiotoxin的II型BK通道（BK α/β4），转变为具有低开放概率和更快门控的对iberiotoxin敏感的I型通道（仅BK α）。癫痫活动后向大多数I型通道表达的转换与BK通道功能在动作电位阈值上的丧失相关，同时保持该通道对早期放电频率增加的作用。使用杂合β4基因敲除小鼠，我们发现表达减少足以增加癫痫敏感性。我们得出结论，癫痫诱导的KCNMB4下调是一种活动依赖性机制，可增加DG神经元的兴奋性。这些新发现表明，BK通道亚型不仅由细胞特异性表达定义，还可根据神经元兴奋性的近期历史而具有可塑性。
