Department of Neurology, University of Wisconsin, Madison, WI, USA.
Comprehensive Epilepsy Center, Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Epilepsia. 2018 Jan;59(1):135-145. doi: 10.1111/epi.13962. Epub 2017 Dec 18.
Childhood absence epilepsy (CAE) is a genetic generalized epilepsy syndrome with polygenic inheritance, with genes for γ-aminobutyric acid (GABA) receptors and T-type calcium channels implicated in the disorder. Previous studies of T-type calcium channel electrophysiology have shown genetic changes and medications have multiple effects. The aim of this study was to use an established thalamocortical computer model to determine how T-type calcium channels work in concert with cortical excitability to contribute to pathogenesis and treatment response in CAE.
The model is comprised of cortical pyramidal, cortical inhibitory, thalamocortical relay, and thalamic reticular single-compartment neurons, implemented with Hodgkin-Huxley model ion channels and connected by AMPA, GABA , and GABA synapses. Network behavior was simulated for different combinations of T-type calcium channel conductance, inactivation time, steady state activation/inactivation shift, and cortical GABA conductance.
Decreasing cortical GABA conductance and increasing T-type calcium channel conductance converted spindle to spike and wave oscillations; smaller changes were required if both were changed in concert. In contrast, left shift of steady state voltage activation/inactivation did not lead to spike and wave oscillations, whereas right shift reduced network propensity for oscillations of any type.
These results provide a window into mechanisms underlying polygenic inheritance in CAE, as well as a mechanism for treatment effects and failures mediated by these channels. Although the model is a simplification of the human thalamocortical network, it serves as a useful starting point for predicting the implications of ion channel electrophysiology in polygenic epilepsy such as CAE.
儿童失神癫痫（CAE）是一种具有多基因遗传的遗传性全面性癫痫综合征，γ-氨基丁酸（GABA）受体和 T 型钙通道基因与该疾病有关。先前对 T 型钙通道电生理学的研究表明遗传变化和药物具有多种作用。本研究旨在使用已建立的丘脑皮质计算机模型来确定 T 型钙通道如何与皮质兴奋性协同作用，以促进 CAE 的发病机制和治疗反应。
该模型由皮质锥体、皮质抑制、丘脑皮质中继和丘脑网状单室神经元组成，采用 Hodgkin-Huxley 模型离子通道，并通过 AMPA、GABA 和 GABA 突触连接。为不同的 T 型钙通道电导、失活时间、稳态激活/失活移位和皮质 GABA 电导组合模拟网络行为。
降低皮质 GABA 电导和增加 T 型钙通道电导将纺锤波转换为棘波和慢波振荡；如果两者同时变化，则需要更小的变化。相比之下，稳态电压激活/失活的左移不会导致棘波和慢波振荡，而右移会降低任何类型振荡的网络倾向。
这些结果为 CAE 多基因遗传的机制提供了一个窗口，以及这些通道介导的治疗效果和失败的机制。尽管该模型是对人类丘脑皮质网络的简化，但它是预测多基因癫痫（如 CAE）离子通道电生理学影响的有用起点。
