Transcriptional Regulation of Channelopathies in Genetic and Acquired Epilepsies

Abstract

Epilepsy is a common neurological disorder characterized by recurrent uncontrolled seizures and has an idiopathic "genetic" etiology or a symptomatic "acquired" component. Genetic studies have revealed that many epilepsy susceptibility genes encode ion channels, including voltage-gated sodium, potassium and calcium channels. The high prevalence of ion channels in epilepsy pathogenesis led to the causative concept of "ion channelopathies," which can be elicited by specific mutations in the coding or promoter regions of genes in genetic epilepsies. Intriguingly, expression changes of the same ion channel genes by augmentation of specific transcription factors (TFs) early after an insult can underlie acquired epilepsies. In this study, we review how the transcriptional regulation of ion channels in both genetic and acquired epilepsies can be controlled, and compare these epilepsy "ion channelopathies" with other neurodevelopmental disorders.

Revisiting the Impact of Neurodegenerative Proteins in Epilepsy: Focus on Alpha-Synuclein, Beta-Amyloid, and Tau

“…[2]. There is an increased understanding of the contribution of neuroinflammation, channelopathies, neurodegeneration, neurogenesis, neural reorganization, and plasticity in epilepsy [10,11]. In recent years, several findings have repeatedly reinforced the role of neuroinflammation in epilepsy [7,12,13], indicating that targeting brain inflammation might be a possible therapeutic strategy against epilepsy.…”

“…Epilepsy also exhibits idiopathic "genetic" etiology or symptomatic "acquired" elements. Several susceptibility genes encoding ion channels, including voltage-gated sodium, potassium, and calcium channels, have been unraveled from genetic investigations [11]. Mutations in three alpha subunit genes (SCN1A, SCN2A, SCN8A) of the voltage-gated sodium channels (VGSCs) have been implicated in epilepsy [16].…”

Highly dynamic inflammatory and excitability transcriptional profiles in hippocampal CA1 following status epilepticus

“…Activation of TFs is one of the earliest responses following a brain insult 36 . Recently, we have identified several key transcriptional control mechanisms of CA1 pyramidal burst firing activity, namely transcriptional activation by the transcription factors Metal Regulatory Transcription Factor 1 (Mtf1) and Early Growth Response 1 (Egr1) 7 , 37 .…”

Perspectives on Understanding Aberrant Brain Networks in Epilepsy

“…a) Vertex aberrance: Most prior work in epilepsy conceived aberrance to arise from a seizure focus, which can be regarded as a vertex (or a group of vertices). These prior studies reported abnormalities in cell dynamics caused by channelopathies (van Loo and Becker, 2020), or changes in the structure of a brain region, such as a focal cortical dysplasia (Gill et al, 2021;Sinha and Davis, 2021) or hippocampal sclerosis (Winston et al, 2013;Chen et al, 2018). b) Edge aberrance: Altered connections between neurons or areas can be caused by changes in conduction velocities, which could occur due to changes in myelination, or by changes in synaptic dynamics.…”