Perisomatic Inhibitory Network Dysfunction in Neurological Disease

描述（由申请人提供）：在美国，估计每年有20万例新的癫痫病例被诊断出来。颞叶癫痫是最常见的癫痫综合征，通常在早期无端癫痫发作后发生，并且对主流抗癫痫药物特别耐药。海马齿状回是颞叶癫痫的特征性结构和功能变化的核心。GABA能中间神经元的体周投射网络调节齿状投射神经元（颗粒细胞）的兴奋性。抑制性网络的活性和同步性由间隙连接和GABA能化学连接的组合控制。然而，是否GABA能抑制和电耦合的perisomatic中间神经元之间的修改在癫痫的发展过程中，癫痫网络活动的不稳定性的基础还有待研究。此外，中间神经元之间的抑制和电耦合的动态变化可能决定癫痫发作的持续时间和蔓延。了解癫痫持续状态后躯体周围抑制网络的活动模式如何改变，以及癫痫发作期间的动态调节，将有助于评估间隙连接和GABA受体的药理学操作是否能有效治疗癫痫。这个建议的假设是，癫痫持续状态（SE）改变非突触和突触之间的快速尖峰的体周齿状中间神经元的相互抑制，从而增强相互抑制，其中妥协的反馈抑制投射神经元的耦合。有人进一步提出，调制抑制电流和电耦合的pH值的变化，伴随神经元的活动破坏perisomatic抑制神经元活动增强齿状兴奋性和癫痫发生。该研究将使用毛果芸香碱诱导的癫痫持续状态来模拟获得性癫痫的发展，并结合解剖学，生理学和计算方法来解决以下具体问题。目的1将确定存在的紧张性GABA电流的快速尖峰篮细胞和检查是否后状态增强紧张性GABA电流妥协颗粒细胞的体周抑制。目的2将确定篮细胞之间突触和电耦合的后状态变化及其对齿状网络兴奋性和同步性的影响。目的3将测试是否活动依赖性调制篮细胞突触和非突触耦合的酸性pH值变化伴随神经元活动破坏抑制和癫痫持续状态后癫痫发生。预计这项研究将确定获得性癫痫中齿状网络活动动态不稳定的基本机制。

DESCRIPTION (provided by applicant): An estimated 200,000 new cases of epilepsy are diagnosed each year in the United States. Temporal lobe epilepsy, the most common epileptic syndrome, often develops following early unprovoked seizures and is particularly resistant to mainstream antiepileptic drugs. The hippocampal dentate gyrus is at the heart of the characteristic structural and functional changes that underlie temporal lobe epilepsy. A network of perisomatically projecting GABAergic interneurons regulates the excitability of dentate projection neurons, the granule cells. Activity and synchrony of inhibitory networks are governed by a combination of gap junctional and GABAergic chemical connections. However, whether GABAergic inhibition and electrical coupling among the perisomatic interneurons are modified during development of epilepsy and underlie the instability in network activity in epilepsy is yet to be examined. Additionally, dynamic changes in inhibitory and electrical coupling among interneurons are likely to determine the duration and spread of seizures. Understanding how activity patterns in the perisomatic inhibitory network are altered following status epilepticus and dynamically regulated during seizures will help evaluate whether pharmacological manipulation of gap junctions and GABA receptors would be effective in treating epilepsy. The hypothesis of this proposal is that status epilepticus (SE) alters non-synaptic and synaptic coupling between fast-spiking perisomatic dentate interneurons resulting in enhanced mutual inhibition which compromises feedback inhibition of projection neurons. It is further proposed that modulation of inhibitory currents and electrical coupling by pH changes that accompany neuronal activity undermine perisomatic inhibition during neuronal activity enhancing dentate excitability and contributing to epileptogenesis. The study will use pilocarpine induced status epilepticus to model development of acquired epilepsy, and a combination of anatomical, physiological and computational approaches to address the following specific questions. Aim 1 will identify the presence of tonic GABA currents in fast-spiking basket cells and examine whether post-status enhancement of tonic GABA currents compromise perisomatic inhibition of granule cells. Aim 2 will identify post-status changes in synaptic and electrical coupling among basket cells and their effects on dentate network excitability and synchrony. Aim 3 will test whether activity-dependent modulation of basket cell synaptic and non-synaptic coupling by acidic pH shifts accompanying neuronal activity undermines inhibition and contributes to epileptogenesis after status epilepticus. It is anticipated that the study will identify fundamental mechanisms underlying dynamical instability of dentate network activity in acquired epilepsy.