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.
Highlights
It is well established that seizures alter the milieu of ion channels and transporters in neurons, some of which are pro-inhibitory and protect against subsequent seizures, whereas others are pro-excitatory and contribute to epileptogenesis
Similar effects from two different chemoconvulsants indicate that increases in neuronal excitability, rather than the pilocarpine or kainic acid per se, underlie decreases in KCNMB4 mRNA expression
We found a significant decrease in EGFP fluorescence in pilocarpine-treated mice, albeit not to the extent of mRNA reductions assayed by PCR, perhaps due to a slower turnover of conventional EGFP protein [23]
Summary
It is well established that seizures alter the milieu of ion channels and transporters in neurons, some of which are pro-inhibitory and protect against subsequent seizures, whereas others are pro-excitatory and contribute to epileptogenesis. Changes in ion channels are observed, including inward rectifiers and HCN channels, which provide an adaptive response following seizures [1,2,3,4,5]. Following a single seizure, blocking BK channels protects against subsequent seizures [6]. Supporting the concept that BK channels can be pro-excitatory is the finding that humans with a gain-of-function point mutation of the poreforming α subunit (Kcnma1) have epileptic seizures [8]. Action potential (AP) frequency is increased in hypothalamic neurons expressing a gain-of-function BK channel in transgenic mice [9]
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