Perisomatic Inhibitory Network Dysfunction in Neurological Disease

神经系统疾病中的体周抑制网络功能障碍

• 批准号: 8893168
• 负责人: Vijayalakshmi Santhakumar
• 金额: $ 34.78万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2018-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8893168
• 关键词: Address; Adopted; Affect; Age; Antiepileptic Agents; Behavior; Buffers; Characteristics; Chemicals; Coupling; Data; Development; Diagnosis; Disease; Drug Targeting; Drug resistance; Epilepsy; Epileptogenesis; Feedback; GABA Receptor; GABA transporter; Gap Junctions; Genetic; Goals; Heart; Hippocampus (Brain); Interneurons; Kinetics; Lead; Mainstreaming; Measures; Mus; Myoepithelial cell; Nature; Neurons; Parvalbumins; Patients; Pattern; Physiological; Pilocarpine; Quality of life; Rattus; Resistance; Risk; Rodent; Seizures; Slice; Status Epilepticus; Synapses; Syndrome; Temporal Lobe Epilepsy; Testing; United States; alternative treatment; computer studies; dentate gyrus; extracellular; gamma-Aminobutyric Acid; granule cell; inhibitory neuron; large scale simulation; model development; nervous system disorder; network dysfunction; network models; novel; research study; simulation

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.

描述（由申请人提供）：据估计，美国每年诊断出 200,000 例新的癫痫病例。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，并且对主流抗癫痫药物特别耐药。海马齿状回是颞叶癫痫特征性结构和功能变化的核心。体周围投射的 GABA 能中间神经元网络调节齿状投射神经元（颗粒细胞）的兴奋性。抑制网络的活性和同步性由间隙连接和 GABA 化学连接的组合控制。然而，在癫痫的发展过程中，体周中间神经元之间的 GABA 能抑制和电耦合是否发生改变，并成为癫痫网络活动不稳定的基础，仍有待研究。此外，中间神经元之间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扩散。了解癫痫持续状态后体周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。该提议的假设是癫痫持续状态（SE）改变快速尖峰周齿状中间神经元之间的非突触和突触耦合，导致增强的相互抑制，从而损害投射神经元的反馈抑制。进一步提出，伴随神经元活动的pH变化对抑制电流和电耦合的调节破坏了神经元活动期间的体周抑制，增强了齿状兴奋性并有助于癫痫发生。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。目标 1 将识别快速尖峰篮细胞中强直 GABA 电流的存在，并检查强直 GABA 电流的状态后增强是否会损害颗粒细胞的体周抑制。目标 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。目标 3 将测试伴随神经元活动的酸性 pH 变化对篮子细胞突触和非突触耦合的活动依赖性调节是否会破坏抑制并有助于癫痫持续状态后的癫痫发生。预计该研究将确定获得性癫痫中齿状网络活动动态不稳定性的基本机制。