An Acquired Channelopathy Involving Thalamic T-Type Ca²⁺Channels after Status Epilepticus

Abstract

Some epilepsies are linked to inherited traits, but many appear to arise through acquired alterations in neuronal excitability. Status epilepticus (SE) is associated with numerous changes that promote spontaneous recurrent seizures (SRS), and studies have suggested that hippocampal T-type Ca 2ϩ channels underlie increased bursts of activity integral to the generation of these seizures. The thalamus also contributes to epileptogenesis, but no studies have directly assessed channel alterations in the thalamus during SE or subsequent periods of SRS. We therefore investigated longitudinal changes in thalamic T-type channels in a mouse pilocarpine model of epilepsy. T-type channel gene expression was not affected during SE; however Ca V 3.2 mRNA was significantly upregulated at both 10 d post-SE (seizure-free period) and 31 d post-SE (SRS-period). Overall T-type current density increased during the SRS period, and the steady-state inactivation shifted from a more hyperpolarized membrane potential during the latent stage, to a more depolarized membrane potential during the SRS period. Ca V 3.2 functional involvement was verified with Ca V 3.2 inhibitors that reduced the native T-type current in mice 31 d post-SE, but not in controls. Burst discharges of thalamic neurons reflected the changes in whole-cell currents, and we used a computational model to relate changes observed during epileptogenesis to a decreased tendency to burst in the seizure-free period, or an increased tendency to burst during the period of SRS. We conclude that SE produces an acquired channelopathy by inducing long-term alterations in thalamic T-type channels that contribute to characteristic changes in excitability observed during epileptogenesis and SRS.

Mapping thalamocortical network pathology in temporal lobe epilepsy

“…25 These synaptic alterations may not only result from cell loss but also from abnormal structural plasticity at the level of single cells. Indeed, a recent study in pilocarpine-induced status epilepticus showed marked long-term increases in T-type calcium channels in the midline region, 26 further supporting a role for altered distribution of receptor channels in thalamic hyperexcitability. Thalamic abnormalities in our patients extended to posterior divisions corresponding to the location of the medial pulvinar.…”

Transcriptional Regulation of T-type Calcium Channel CaV3.2

“…The latter has been demonstrated to relate to the modulation of Ca V 3.2 transcription by REST (16,18). Interestingly, highly dynamic changes of Ca V 3.2 expression have been observed in epileptogenesis after brain insults in thalamic as well as hippocampal principal neurons (14,15). In hippocampal CA1 pyramidal cells, Ca V 3.2 mRNA is transiently up-regulated early in epileptogenesis that is triggered by an episode of status epilepticus (SE), leading to an increase in the propensity for intrinsic burst-firing (15,45).…”

“…Gain-of-function mutations in the Ca V 3.2 gene are associated with idiopathic generalized/absence epilepsy (11)(12)(13). Likewise, acquired increases in thalamic and hippocampal Ca V 3.2 expression contribute to the development of chronic epilepsy (14,15). In addition, overexpression of Ca V 3.2 channels in myocytes may result in the development of several cardiac dysfunctions, including ventricular arrhythmias (16,17).…”

The Role of Calcium Channels in Epilepsy

“…These mice are deficient in one copy of the gene that encodes the presynaptic protein SNAP-25, which interacts with HVA channels. Finally, in the pilocarpine and electrical kindling models of limbic epilepsy, augmented T-type currents are ob-served in CA1 hippocampal neurons, along with increased burst-firing and neuronal death, findings that are attenuated in Ca V 3.2 knockout mice (Faas et al 1996;Hendriksen et al 1997;Su et al 2002;Becker et al 2008;Graef et al 2009). …”