Vinnenberg Laura, Rychlik Nicole, Oniani Tengiz, Williams Brandon, White John A, Kovac Stjepana, Meuth Sven G, Budde Thomas, Hundehege Petra
Department of Neurology with Institute of Translational Neurology, Münster University, Albert-Schweitzer-Campus 1, D-48149 Münster, Germany.
Institute of Physiology I, Münster University, Robert-Koch-Str. 27a, D-48149 Münster, Germany.
Exp Neurol. 2024 Jan;371:114572. doi: 10.1016/j.expneurol.2023.114572. Epub 2023 Oct 16.
Cuprizone (CPZ)-induced alterations in axonal myelination are associated with a period of neuronal hyperexcitability and increased activity of hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels in the thalamocortical (TC) system. Substances used for the treatment of multiple sclerosis (MS) have been shown to normalize neuronal excitability in CPZ-treated mice. Therefore, we aimed to examine the effects of diroximel fumarate (DRF) and the sphingosine 1-phospate receptor (S1PR) modulator siponimod on action potential firing and the inward current (I) carried by HCN ion channels in naive conditions and during different stages of de- and remyelination. Here, DRF application reduced I current density in ex vivo patch clamp recordings from TC neurons of the ventrobasal thalamic complex (VB), thereby counteracting the increase of I during early remyelination. Siponimod reduced I in VB neurons under control conditions but had no effect in neurons of the auditory cortex (AU). Furthermore, siponimod increased and decreased AP firing properties of neurons in VB and AU, respectively. Computational modeling revealed that both DRF and siponimod influenced thalamic bursting during early remyelination by delaying the onset and decreasing the interburst frequency. Thus, substances used in MS treatment normalize excitability in the TC system by influencing AP firing and I.
cuprizone（CPZ）诱导的轴突髓鞘形成改变与丘脑皮质（TC）系统中一段神经元过度兴奋期以及超极化激活的环核苷酸门控（HCN）通道活性增加有关。用于治疗多发性硬化症（MS）的物质已被证明可使CPZ处理的小鼠的神经元兴奋性恢复正常。因此，我们旨在研究富马酸二甲酯（DRF）和鞘氨醇-1-磷酸受体（S1PR）调节剂西尼莫德对未处理状态以及脱髓鞘和再髓鞘化不同阶段的动作电位发放和HCN离子通道携带的内向电流（I）的影响。在此，在离体膜片钳记录中，应用DRF可降低腹侧基底丘脑复合体（VB）的TC神经元的I电流密度，从而抵消早期再髓鞘化期间I的增加。在对照条件下，西尼莫德可降低VB神经元中的I，但对听觉皮层（AU）的神经元没有影响。此外，西尼莫德分别增加和降低了VB和AU中神经元的动作电位发放特性。计算模型显示，DRF和西尼莫德均通过延迟发作起始并降低发作间期频率来影响早期再髓鞘化期间的丘脑爆发。因此，MS治疗中使用的物质通过影响动作电位发放和I来使TC系统中的兴奋性恢复正常。
