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: 8238495
• 负责人: Vijayalakshmi Santhakumar
• 金额: $ 32.46万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8238495
• 关键词: Address; Adopted; Affect; Age; Antiepileptic Agents; Behavior; Buffers; Characteristics; Chemicals; Coupling; Data; Development; Diagnosis; Disease; Drug Delivery Systems; 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. PUBLIC HEALTH RELEVANCE: Acquired temporal lobe epilepsy is a disorder affecting over 1.5 million patients and is associated with long term decrease in quality of life. The experiments proposed in this study will determine if dynamic decreases in inhibition during seizures contributes to prolonged neuronal activity and development of epilepsy. It is expected that understanding the changes in inhibitory circuit function in epilepsy will lead to novel alternatives to manage patients with early unprovoked seizures and reduce the risk for developing epilepsy.

描述（由申请人提供）：在美国，估计每年有200,000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，通常发生在早期无因性癫痫发作之后，对主流抗癫痫药物尤其具有耐药性。海马齿状回是颞叶癫痫的特征性结构和功能变化的核心。细胞周围投射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是由间隙连接和gaba能化学连接的组合控制的。然而，在癫痫的发展过程中，周围中间神经元之间的gaba能抑制和电偶联是否被改变，以及癫痫中网络活动不稳定的基础尚有待研究。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范围。了解在癫痫持续状态和癫痫发作期间动态调节下，胞周抑制网络的活动模式如何改变，将有助于评估对间隙连接和GABA受体的药理学操作是否能有效治疗癫痫。这一建议的假设是，癫痫持续状态（SE）改变了快速尖峰的周围齿状中间神经元之间的非突触和突触耦合，从而增强了相互抑制，从而损害了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偶联的调节破坏了神经元活动期间的细胞周围抑制，增强了齿状兴奋性，并促进了癫痫的发生。该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将确定快速尖峰篮状细胞中强直GABA电流的存在，并检查状态后增强的强直GABA电流是否会损害颗粒细胞的周围抑制。目的2将确定篮状细胞之间突触和电耦合的状态后变化及其对齿状网络兴奋性和同步性的影响。目的3将测试脑篮细胞突触和非突触偶联的活性依赖调节是否通过酸性pH值的变化伴随神经元活动破坏抑制，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神经网络活动动态不稳定的基本机制。