Inhibitory Network Plasticity in Neurological Disease

神经系统疾病中的抑制网络可塑性

• 批准号: 10382235
• 负责人: Vijayalakshmi Santhakumar
• 金额: $ 34.02万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382235
• 关键词: Adult; Affect; Axon; Behavior; Brain; Calcium; Cell physiology; Cells; Computer Models; Data; Development; Disease; Drug resistance; Epilepsy; Epileptogenesis; Experimental Models; Feedback; Genetic; Hilar; Hippocampus (Brain); Human; Image; Impairment; Injury; Interneurons; Knowledge; Label; Literature; Location; Mediating; Memory; Memory impairment; Mission; Molecular; Morphology; Mus; Myoepithelial cell; National Institute of Neurological Disorders and Stroke; Neurons; Optics; Output; Parvalbumins; Pathologic Processes; Pathway interactions; Patients; Pattern; Phase; Physiology; Pilocarpine; Play; Prevention; Regulation; Resistance; Retroviral Vector; Role; Saline; Seizures; Status Epilepticus; Structure; Supporting Cell; Synapses; Temporal Lobe Epilepsy; Testing; Therapeutic; Time; Transgenic Mice; acquired epilepsy; comorbidity; dentate gyrus; disability; excitatory neuron; experimental study; gamma-Aminobutyric Acid; granule cell; hippocampal sclerosis; improved; memory process; molecular marker; morphometry; nervous system disorder; nestin protein; network models; neurogenesis; novel; patch sequencing; place fields; postsynaptic; preference; prevent; recruit; tool; transcriptomics

Project Summary: Temporal lobe epilepsy (TLE) develops in a third of over 300,000 patients with a first seizure and over 30% of cases are resistant to drugs contributing to a significant disability. Presence of a therapeutic time window between the initial insult and development of epilepsy suggests that improved mechanistic understanding of early pathological process may enable prevention of epileptogenesis and associated co-morbidities. While sclerosis of the hippocampal dentate gyrus characterizes late stage TLE, cell loss, network reorganization and deficient inhibition in the dentate gyrus occur soon after insults that progress to TLE. In particular, the dentate inhibitory gate which limits GC activity throughput is compromised early in acquired TLE. However, what cells and circuits make up the dentate inhibitory gate and how this is compromised after seizures is not fully understood. Recently, a new class of neurons, semilunar granule cells (SGCs) were proposed as drivers of sustained dentate feedback inhibition. Although SGC-like neuros are observed in multiple species including humans and are activated during behaviors, the development, molecular identity, and connectivity of SGCs are not known making it difficult to determine their role in dentate function and disease. The limited literature and our pilot data that SGCs input and output connections are distinct from granule cells indicating that they play a unique role in dentate processing. This study will test the hypothesis that SGCs from a parallel dentate circuit that strengthens inhibition in the normal brain. We further propose that cellular and network changes after seizures compromise SGC mediated inhibition and augment their excitatory effects contributing to epilepsy and memory deficits. Combining morphometry, Patch-seq transcriptomics, electro- and optophysiology in transgenic mouse lines subject to experimental epilepsy and computational modeling will allow us to test the above hypothesis. Aim 1 will define the cellular and circuit identity of SGCs and determine molecular markers. Aim 2 will determine if the SGC excitatory circuit is strengthened and feedback inhibitory circuit compromised after status epilepticus. Finally, Aim 3 will examine the normal and seizure-induced development of SGCs and their contribution to dentate memory processing. On completion the studies will eliminate specific knowledge gaps in how the dentate circuit functions in behaviors and epilepsy, in keeping with the NINDS mission, and provide information needed to prevent collapse of dentate inhibition soon after seizures and prevent development of epilepsy and memory co-morbidities.

项目摘要：颞叶癫痫（TLE）在300,000多名患者中有三分之一 癫痫发作和30％以上的病例具有抗药性，导致严重残疾的药物。存在 最初侮辱和癫痫发育之间的治疗时间窗口表明改善了 对早期病理过程的机械理解可以预防癫痫发生和 相关的合并症。海马齿状回的硬化性是晚期tle的特征 损害，网络重组和齿状回的抑制不足发生在侮辱后不久发生 tle。特别是，限制GC活性吞吐量的齿状抑制门在早期就会受到损害 获得的tle。但是，哪些细胞和电路构成齿状抑制门以及如何构成 癫痫发作后遭到妥协。最近，一种新的神经元，半肺颗粒细胞 提出（SGC）作为持续齿状反馈抑制的驱动因素。虽然类似SGC的神经是 在包括人在内的多种物种中观察到，并在行为期间被激活，发育，分子 身份和SGC的连通性尚不清楚，因此很难确定其在齿状功能中的作用 和疾病。 SGCS输入和输出连接的有限文献和我们的试验数据不同于 颗粒细胞表明它们在齿状处理中起着独特的作用。这项研究将检验假设 从平行齿状电路中的SGC可以增强正常大脑的抑制作用。我们进一步提出 癫痫发作后的细胞和网络变化损害SGC介导的抑制并增加了兴奋性 导致癫痫和记忆缺陷的影响。组合形态计量学，斑块序列组学， 经过实验性癫痫和计算的转基因小鼠系中的电生理学 建模将使我们能够检验上述假设。 AIM 1将定义SGC的细胞和电路身份 并确定分子标记。 AIM 2将确定SGC兴奋回路是否得到加强，并且 癫痫持续状态后，反馈抑制回路损害。最后，AIM 3将检查正常和 癫痫发作引起的SGC的发展及其对齿状记忆处理的贡献。完成 这些研究将消除齿状电路如何在行为和 癫痫病，与NINDS任务保持一致，并提供防止齿状崩溃所需的信息 癫痫发作后不久抑制，并防止癫痫和记忆合并症的发展。

项目成果

Fingerprints of Interictal Spikes: Can Imprints Deliver a Verdict on Their Role in Epilepsy?

发作间期尖峰的指纹：印记能否判断其在癫痫中的作用？

• DOI: 10.5698/1535-7597-16.1.41
• 发表时间: 2016
• 期刊: Epilepsy currents
• 影响因子: 3.6
• 作者: Proddutur,Archana;Santhakumar,Viji
• 通讯作者: Santhakumar,Viji

Dentate cannabinoid-sensitive interneurons undergo unique and selective strengthening of mutual synaptic inhibition in experimental epilepsy.

• DOI: 10.1016/j.nbd.2016.01.013
• 发表时间: 2016-05
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Yu J;Swietek B;Proddutur A;Santhakumar V
• 通讯作者: Santhakumar V

Seizure-induced alterations in fast-spiking basket cell GABA currents modulate frequency and coherence of gamma oscillation in network simulations.

• DOI: 10.1063/1.4830138
• 发表时间: 2013-11
• 期刊: Chaos
• 影响因子: 2.9
• 作者: Archana Proddutur;Jiandong Yu;F. Elgammal;V. Santhakumar

Dentate total molecular layer interneurons mediate cannabinoid-sensitive inhibition.

• DOI: 10.1002/hipo.22419
• 发表时间: 2015-08
• 期刊: Hippocampus
• 影响因子: 3.5
• 作者: Yu J;Swietek B;Proddutur A;Santhakumar V
• 通讯作者: Santhakumar V

Distinct effect of impact rise times on immediate and early neuropathology after brain injury in juvenile rats.

• DOI: 10.1002/jnr.23401
• 发表时间: 2014-10
• 期刊: JOURNAL OF NEUROSCIENCE RESEARCH
• 影响因子: 4.2
• 作者: Neuberger, Eric J.;Wahab, Radia Abdul;Jayakumar, Archana;Pfister, Bryan J.;Santhakumar, Vijayalakshmi
• 通讯作者: Santhakumar, Vijayalakshmi