Perisomatic Inhibitory Network Dysfunction in Neurological Disease

描述(由申请人提供)：据估计，美国每年新诊断的癫痫病例为20万例。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，对主流抗癫痫药物特别耐药。海马齿状回是导致颞叶癫痫的结构和功能改变的核心。一个异构性投射的GABA能中间神经元网络调节齿状投射神经元即颗粒细胞的兴奋性。抑制网络的活性和同步性由缝隙连接和GABA能化学连接共同控制。然而，GABA能抑制和周围中间神经元之间的电耦合是否在癫痫的发展过程中发生了改变，并成为癫痫网络活动不稳定的基础，这一点还有待研究。此外，中间神经元之间抑制性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，体周抑制网络的活动模式是如何改变的，并在癫痫发作过程中进行动态调节，这将有助于评估缝隙连接和GABA受体的药理操作是否对癫痫有效。该假说认为癫痫持续状态(SE)改变了快速放电的齿状体周间神经元之间的非突触和突触耦合，导致相互抑制增强，从而影响投射神经元的反馈抑制。进一步提出，伴随着神经元活动的pH变化对抑制电流和电耦合的调节破坏了神经元活动过程中的体周抑制，增强了齿状突起的兴奋性，并有助于癫痫的发生。这项研究将使用匹罗卡品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鉴定快速刺激性篮子细胞中强直的GABA电流的存在，并检查紧张性GABA电流的增强是否影响颗粒细胞的周身抑制。目的2将确定状态后篮子细胞间突触和电耦合的变化及其对齿状网络兴奋性和同步性的影响。目的3将测试酸性pH变化对篮细胞突触和非突触偶联的活动依赖的调节是否会破坏抑制，并在癫痫持续状态后参与癫痫的发生。预计这项研究将确定获得性癫痫患者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.