Demyelination is coupled to neuronal hyperexcitability leading to seizures

认知障碍在原发性进展性MS期间发生且更普遍[1]。虽然MS临床 虽然呈现形式多变，但流行病学研究表明，MS患者的发病率是其他患者的三到六倍， 比一般人更容易患上癫痫海马中的兴奋性毒性神经元损伤（以及 其他区域）被认为是近50%多发性硬化症（MS）认知缺陷的原因之一 患者，可能是由于谷氨酸代谢障碍。谷氨酸是脑内主要的兴奋性神经递质， 哺乳动物中枢神经系统我们最近发表的结果表明：i）抑制性小清蛋白神经元减少， 慢性铜腙饮食喂养的脱髓鞘小鼠（Lapato等，2016）和MS患者的海马中， 癫痫发作（Lapato等人，2020）; ii）星形胶质细胞谷氨酸摄取和水稳态失调， 癫痫发作的MS患者的海马体（Lapato等人，2020）[4]。本申请的目的是 了解脱髓鞘诱导的抑制性神经元损失如何影响海马变化， 学习和记忆缺陷。我们假设慢性脱髓鞘导致海马PV减少， 神经元和指标的重大变化，突触传递参与学习和记忆。目标1：我们 将确定慢性铜腙饮食脱髓鞘诱导的长时程增强的变化， 脑切片的电生理学。在aim 2中，我们将研究慢性脱髓鞘过程中突触的变化， 海马的CA 1和纹状体辐射区。在目标3中，我们将评估慢性脱髓鞘诱导的 学习和记忆的变化。我们预计这项研究将是变革性的，因为我们将介绍 该研究共同体的功能和分子机制的记忆障碍，由于脱髓鞘。

Cognitive impairment occurs and is more prevalent during primary progressive MS[1]. While MS clinical presentation is protean, epidemiological studies have revealed that MS patients are three to six times more likely to develop epileptic seizures than the population at large. Excitotoxic neuronal damage in the hippocampus (and other regions) is thought to be one of the causes for cognitive deficits in nearly 50% of multiple sclerosis (MS) patients and could be due glutamate dyshomeostasis. Glutamate is a major excitatory neurotransmitter in the mammalian CNS. Our recent published results have shown i) a decrease in inhibitory parvalbumin neurons of chronic cuprizone-diet fed demyelinating mice (Lapato et al., 2016) and in the hippocampus of MS patients with seizures (Lapato et al., 2020); ii) astrocyte glutamate uptake and water homeostasis are dysregulated in the hippocampus of MS patients with seizures (Lapato et al., 2020)[4]. The objective of this application is to understand how demyelination-induced loss of inhibitory neurons impacts hippocampal changes that lead to learning and memory deficits. We hypothesize that chronic demyelination induces decrease in hippocampus PV neurons and indices substantial changes in synaptic transmission involved in learning and memory. In aim 1: we will determine chronic cuprizone diet-demyelination induced changes in long term potentiation by electrophysiology in brain slices. In aim 2, we will examine synaptic changes during chronic demyelination in the CA1 and striatum radiatum regions of the hippocampus. In aim 3, we will assess chronic demyelination induced changes in learning and memory. We anticipate that this research will be transformative, as we will introduce to the research community a functional and molecular mechanism for memory disorder due to demyelination.