Cellular and Circuit Mechanisms of Temporal Lobe Epilepsy

颞叶癫痫的细胞和回路机制

基本信息

批准号：
9308338
负责人：
James O. McNamara
金额：
$ 43.05万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9308338
关键词：
Address Adult Amygdaloid structure Anatomy Anticonvulsants Area Axon Brain-Derived Neurotrophic Factor Calcium Clinical Research Development Disease Electroencephalography Endocannabinoids Epilepsy Excitatory Synapse Frequencies Glutamates Hippocampus (Brain)Human Infusion procedures Interneurons Kainic Acid Lead Locales Long-Term Depression Long-Term Potentiation Modeling Modification Molecular Mus Neurotrophic Tyrosine Kinase Receptor Type 2 Permeability Pilocarpine Presynaptic Terminals Preventive Pyramidal Cells Recovery Recurrence Resistance Role Seizures Signal Pathway Signal Transduction Site Slice Status Epilepticus Stratum Lucidum Synapses Synaptic plasticity Temporal Lobe Temporal Lobe Epilepsy Testing Tetanus Toxin Transgenic Organisms Vertebral column Whole-Cell Recordings base granule cell improved insight mossy fiber mouse model optogenetics postsynaptic preclinical study presynaptic prevent receptor release factor selective expression

项目摘要

Epilepsy arising from the temporal lobes is particularly devastating because it is both common and commonly resistant to symptomatic therapy with anticonvulsants. Preclinical and clinical studies support the idea that an episode of status epilepticus followed by recovery contributes to development of temporal lobe epilepsy months or years later. Insight into the mechanisms by which status epilepticus induces temporal lobe epilepsy may facilitate developing preventive and/or disease modifying therapies. We recently discovered a molecular signaling pathway by which status epilepticus induces temporal lobe epilepsy, namely activation of the brain- derived neurotrophic factor receptor, TrkB. A major unresolved question, to be addressed in this application, is how this signaling is transformed into the cellular and circuit modifications that underlie temporal lobe epilepsy. The anatomic locale at which status epilepticus induced activation of TrkB provides a valuable clue to the cellular consequences. The principal site was the synaptic boutons of the mossy fiber axons of hippocampal dentate granule cells. The objective of this application is to test three facets of our unifying hypothesis: a) that status epilepticus induces plasticities of mossy fiber synapses with both CA3 pyramidal cells and inhibitory interneurons; b) that status epilepticus induction of these plasticities requires TrkB; and c) that transmitter release from the mossy fibers underlies expression of temporal lobe epilepsy.

颞叶引起的癫痫尤其具有破坏性，因为它既常见又普遍对抗惊厥药物的对症治疗有抵抗力。临床前和临床研究支持以下观点：癫痫持续状态发作后恢复有助于颞叶癫痫的发展或多年后。深入了解癫痫持续状态诱发颞叶癫痫的机制可能促进预防性和/或疾病改变疗法的开发。我们最近发现了一种分子癫痫持续状态诱发颞叶癫痫的信号通路，即大脑的激活衍生神经营养因子受体，TrkB。本申请要解决的一个未解决的主要问题，就是这种信号传导如何转化为颞叶基础的细胞和电路修饰癫痫。癫痫持续状态诱导 TrkB 激活的解剖部位提供了有价值的线索细胞后果。主要部位是苔藓纤维轴突的突触纽扣海马齿状颗粒细胞。该应用程序的目的是测试我们统一的三个方面假设：a) 癫痫持续状态诱导 CA3 锥体的苔藓纤维突触可塑性细胞和抑制性中间神经元； b) 这些可塑性的癫痫持续状态诱导需要 TrkB；和c) 苔藓纤维释放的递质是颞叶癫痫表现的基础。