Ahmed Maliha, Campbell Sue Ann
Department of Applied Mathematics, and Centre for Theoretical Neuroscience, University of Waterloo, 200 University Avenue W, Waterloo, N2L 3G1, ON, Canada.
J Comput Neurosci. 2025 Mar;53(1):115-130. doi: 10.1007/s10827-024-00887-x. Epub 2024 Dec 21.
Childhood absence epilepsy (CAE) is a paediatric generalized epilepsy disorder with a confounding feature of resolving in adolescence in a majority of cases. In this study, we modelled how the small-scale (synapse-level) effect of progesterone metabolite allopregnanolone induces a large-scale (network-level) effect on a thalamocortical circuit associated with this disorder. In particular, our goal was to understand the role of sex steroid hormones in the spontaneous remission of CAE. The conductance-based computational model consisted of single-compartment cortical pyramidal, cortical interneurons, thalamic reticular and thalamocortical relay neurons, each described by a set of ordinary differential equations. Excitatory and inhibitory synapses were mediated by AMPA, GABAa and GABAb receptors. The model was implemented using the NetPyne modelling tool and the NEURON simulator. It was found that the action of allopregnanolone (ALLO) on individual GABAa-receptor mediated synapses can have an ameliorating effect on spike-wave discharges (SWDs) associated with absence seizures. This effect is region-specific and most significant in the thalamus, particularly the synapses between thalamic reticular neurons. The remedying effect of allopregnanolone on SWDs may possibly be true only for individuals that are predisposed to remission due to intrinsic connectivity differences or differences in tonic inhibition. These results are a useful first-step and prescribe directions for further investigation into the role of ALLO together with these differences to distinguish between models for CAE-remitting and non-remitting individuals.
儿童失神癫痫（CAE）是一种小儿全身性癫痫疾病，其一个令人困惑的特征是在大多数情况下会在青春期缓解。在本研究中，我们模拟了孕酮代谢物别孕烯醇酮的小规模（突触水平）效应如何对与该疾病相关的丘脑皮质回路产生大规模（网络水平）效应。特别是，我们的目标是了解性类固醇激素在CAE自然缓解中的作用。基于电导的计算模型由单室皮质锥体神经元、皮质中间神经元、丘脑网状神经元和丘脑皮质中继神经元组成，每个神经元都由一组常微分方程描述。兴奋性和抑制性突触由AMPA、GABAa和GABAb受体介导。该模型使用NetPyne建模工具和NEURON模拟器实现。研究发现，别孕烯醇酮（ALLO）对单个GABAa受体介导的突触的作用可对与失神发作相关的棘波放电（SWD）产生改善作用。这种效应具有区域特异性，在丘脑中最为显著，特别是丘脑网状神经元之间的突触。别孕烯醇酮对SWD的补救作用可能仅对由于内在连接差异或强直抑制差异而易于缓解的个体成立。这些结果是有用的第一步，并为进一步研究ALLO的作用以及这些差异以区分CAE缓解型和非缓解型个体的模型指明了方向。
