Role of Perineuronal Nets in Epilepsy

项目摘要/摘要 全世界约有5000万人患有癫痫，这是一种以反复发作为特征的综合征， 无缘无故的癫痫发作，表现为行为改变和异常放电 大脑中的神经元群体。癫痫发作是由于兴奋-抑制(E-I)平衡受损引起的。 增强抑制性GABA能功能是一种常用的药理策略。不足为奇的是， 大脑皮质和海马区的GABA能中间神经元已经得到了很好的研究，它们在抑制 从这些结构中产生的兴奋性输出是公认的。GABA能中间神经元倾向于快速刺激性细胞 (高达800赫兹！)，通过每个动作电位的高水平活动来补偿它们的数量较少 导致GABA从它们的终端释放。这些快速放电的神经元大部分都被一层 120多年前高尔基人称之为神经周围神经网络(PNNS)的致密细胞外基质。这些是 由糖胺葡聚糖组成，带负电荷的糖蛋白由一个蛋白质超家族形成 覆盖胞体、近端树突和轴突起始段。它们的作用并不广为人知，但被认为有助于 在细胞分化、神经保护和皮质可塑性方面。在上一个研究肿瘤的资助周期中- 与癫痫相关，我们有了一个意想不到的发现，表明三叉神经核改变了神经细胞膜 电容，使它们能够以超生理速度开火。特别是，从细胞中释放的蛋白水解酶 肿瘤消化PNNS，从而增加膜电容，减缓抑制性神经元的放电速度， 导致癫痫发作。我们现在假设PNNS可能更普遍地成为获得性癫痫的目标， 细胞外基质的蛋白分解和组织重塑是常见的。因此，我们建议对PNN进行研究 整体性及其在不同获得性癫痫小鼠模型中更广泛地在癫痫发生中的作用 癫痫患者的组织。我们假设PNNS定义了星形胶质细胞在突触附近的位置 有助于离子和神经递质摄取；从反应性星形胶质细胞释放基质降解酶 摧毁PNN，从而降低他们的射击速度。这些变化加在一起可能会导致癫痫。这些研究是 在概念上是新颖的，可能会提出一种完全不同的癫痫治疗方法，即靶向 蛋白水解酶，以改善这种疾病。

PROJECT SUMMARY/ABSTRACT Approximately 50 million people worldwide live with epilepsy, a syndrome characterized by repeated, unprovoked seizures that manifest with a combination of altered behavior and abnormal electric discharges of populations of neurons in the brain. Seizures result from impairment of excitatory-inhibitory (E-I) balance. Enhancement of inhibitory GABAergic function is a common pharmacological strategy. Not surprisingly, GABAergic interneurons in the cortex and hippocampus have been well studied, and their role in dampening excitatory output from these structures is well established. GABAergic interneurons tend to be fast-spiking cells (up to 800Hz!), which compensate for their small number by a high level of activity with each action potential causing GABA release from their terminals. A majority of these fast-spiking neurons are surrounded by a layer of dense extracellular matrix that Golgi termed perineuronal nets (PNNs) over 120 years ago. These are composed of glycosaminoglycanes, negatively charged glycoproteins formed from a superfamily of proteins that cover the cell soma, proximal dendrites and axon initial segment. Their role is not well known but believed to aid in cell differentiation, neural protection and cortical plasticity. During the last grant cycle studying tumor- associated epilepsy, we made an unexpected discovery suggesting that PNNs alter the neuronal membrane capacitance, allowing them to fire at supra-physiological rates. Specially, proteolytic enzymes released from the tumor digest PNNs, thereby increasing membrane capacitance and slowing the firing rates of inhibitory neurons, leading to seizures. We now hypothesize that PNNs may be more generally the target of acquired epilepsy, where proteolysis of extracellular matrix and tissue remodeling are common. Hence, we propose to study PNN integrity and its role in epileptogenesis more broadly across different mouse models of acquired epilepsy and in tissues from epilepsy patients. We hypothesize that PNNs define the placement of astrocytes near synapses to aid uptake of ions and neurotransmitters; that release of matrix-degrading enzymes from reactive astrocytes destroy PNNs, thereby slowing their firing rate. Together these changes may lead to epilepsy. These studies are conceptually novel and may suggest a completely different treatment approach to epilepsy, namely targeting proteolytic enzymes to ameliorate this disease.