Downregulation of KCNMB4 expression and changes in BK channel subtype in hippocampal granule neurons following seizure activity

Luke E. Whitmire, Ling Ling, Vladslav Bugay, Chase M. Carver, Santosh Timilsina, Hui Hsiu Chuang, David B. Jaffe, Mark S. Shapiro, Jose E. Cavazos, Robert Brenner

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere0188064
JournalPloS one
Volume12
Issue number11
DOIs
StatePublished - Nov 2017

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Fingerprint Dive into the research topics of 'Downregulation of KCNMB4 expression and changes in BK channel subtype in hippocampal granule neurons following seizure activity'. Together they form a unique fingerprint.

Cite this