Role of hippocampal interneurons in aberrant neurogenesis and epilepsy after traumatic brain injury

海马中间神经元在脑外伤后异常神经发生和癫痫中的作用

• 批准号: 10590467
• 负责人: CORWIN BUTLER
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590467
• 关键词: Acute; Adult; Affect; Anatomy; Animal Model; Animals; Area; Automobile Driving; Brain; Brain Injuries; Brain region; Calcium Channel; Cell Maturation; Cell physiology; Cells; Clinical Data; Communities; Data; Development; Disease; Electrophysiology (science); Epilepsy; Epileptogenesis; Failure; Frequencies; Functional disorder; Funding; Future; Genetic; Goals; Hilar; Hippocampus; Histologic; Homeostasis; Injury; Interneurons; Intervention; Knowledge; Label; Learning; Life; Link; Measures; Medial; Mediating; Mediator; Medical; Membrane Potentials; Memory; Middle East; Military Personnel; Modeling; Monitor; Mus; Myoepithelial cell; Neurons; Neurosciences; Output; Parvalbumins; Pathogenesis; Pathway interactions; Patients; Pharmacogenetics; Phase; Play; Population; Post-Traumatic Epilepsy; Predisposition; Prevention strategy; Process; Proliferating; Recurrence; Regulation; Research; Research Personnel; Rest; Retroviral Vector; Retroviridae; Role; Seizures; Signal Transduction; Slice; Structure; Synapses; Techniques; Temporal Lobe Epilepsy; Testing; Training; Transgenic Mice; Trauma; Traumatic Brain Injury; Veterans; Viral; Work; adult neurogenesis; calcium indicator; cohort; combat; controlled cortical impact; dentate gyrus; entorhinal cortex; epileptiform; experience; experimental study; gamma-Aminobutyric Acid; granule cell; improved; improved outcome; in vivo; injured; mouse model; nerve supply; nervous system disorder; neuroblast; neurogenesis; neuronal circuitry; neurotransmitter release; novel therapeutic intervention; optogenetics; patient population; pharmacologic; preservation; presynaptic; prevent; programs; receptor; recruit; response; selective expression; sham surgery; therapeutic development; translational approach; translational study; treatment strategy

Abstract Post-traumatic epilepsy (PTE) can result from combat-related traumatic brain injury (TBI), a well-documented phenomenon that has caused substantial neurologic disease in Veterans, most recently in relation to conflicts in the Middle East (>350,000 cases of combat-related TBI since 2000). Unfortunately, current treatments for PTE are of limited efficacy, and thus many Veterans with PTE do not have effective seizure control. PTE often manifests as a form of temporal lobe epilepsy, which involves cellular and functional circuit alterations in the hippocampal region of the brain. In the healthy hippocampus, dentate granule cells (DGCs) form a principal cell layer that prevent hyperexcitability through their low firing frequency and relatively hyperpolarized resting membrane potentials. Additionally, the dentate gyrus is a region of ongoing neurogenesis, in which new DGCs are generated throughout adult life and integrate into the existing circuitry, in a process critical to learning and memory. TBI and epilepsy involve the aberrant maturation and integration of adult-born DGCs in the hippocampus, which is thought to disrupt hippocampal function and increase brain excitability leading to seizures. In this region, parvalbumin-positive (PV+) inhibitory basket interneurons not only mediate feed-forward inhibition, but release the neurotransmitter GABA onto immature granule cells and neuroblasts, which modulates circuit integration of these cells as they mature in the hippocampus. Although these interneurons are preserved in many animal models of epilepsy, PV+ basket cells undergo numerous functional and network changes, including reduced excitatory input, increased output failure, and presynaptic calcium channel dysfunction. Prior hypotheses have examined the potential direct contribution of PV+ cell dysfunction to hippocampal hyperexcitability after TBI. In this proposal, I hypothesize that dysfunction of PV+ basket cells after TBI contributes indirectly to hyperexcitability, by driving aberrant maturation and integration of adult-born DGCs. I will investigate how TBI impacts PV+ basket cell function at the cellular and network level, how this dysfunction influences development and integration of adult-born DGCs, and whether changes in PV-cell specific microcircuit structure and function drive whole animal seizure susceptibility following TBI. This proposal will use transgenic mice to selectively target the PV+ basket cell population for expression of calcium indicators, excitatory channelrhodopsins, or specific synthetic receptors to measure PV-cell specific network activity after TBI, as well as the functional outputs of these cells. I will also combine these techniques with retrovirus-mediated labeling of adult-born DGCs, to determine whether changes in post-TBI PV+ basket cell function alter the maturation, integration, or circuit dynamics of adult-born DGCs after TBI. Finally, I will manipulate activity of the PV+ basket cells in vivo to assess their role in neuronal circuit rewiring after TBI, and modulate their activity after TBI in hopes of reducing seizure susceptibility. The knowledge gathered from this study will help guide future work that will refine our understanding of interneuron dysfunction for post-TBI injured Veterans using clinical data, which might one day be able to prevent the development of PTE.

抽象的 创伤后癫痫 (PTE) 可能是由战斗相关的创伤性脑损伤引起的 (TBI)，一种有据可查的现象，已导致严重的神经系统疾病 退伍军人，最近与中东冲突有关（超过 350,000 起案件） 自 2000 年起与战斗相关的 TBI）。不幸的是，目前 PTE 的治疗方法有限 效，因此许多患有 PTE 的退伍军人无法有效控制癫痫发作。英语口语考试 通常表现为颞叶癫痫的一种形式，涉及细胞和 大脑海马区功能回路的改变。在健康的情况下 海马体中，齿状颗粒细胞 (DGC) 形成主要细胞层，可防止 由于其低放电频率和相对超极化的静息状态而导致过度兴奋 膜电位。此外，齿状回是一个持续的区域 神经发生，其中新的 DGC 在整个成年生活中产生并整合到 现有的电路，在对学习和记忆至关重要的过程中。 TBI 和癫痫 涉及海马体中成年 DGC 的异常成熟和整合， 这被认为会破坏海马功能并增加大脑兴奋性 癫痫发作。在该区域，小白蛋白阳性 (PV+) 抑制篮中间神经元不 仅介导前馈抑制，但将神经递质 GABA 释放到 未成熟的颗粒细胞和神经母细胞，调节这些细胞的电路整合 细胞在海马体中成熟。尽管这些中间神经元被保存在 许多癫痫动物模型中，PV+篮细胞经历了许多功能和 网络变化，包括兴奋性输入减少、输出失败增加，以及 突触前钙通道功能障碍。先前的假设已经检验了潜在的 PV+细胞功能障碍对TBI后海马过度兴奋的直接影响。在 根据这个建议，我假设 TBI 后 PV+ 篮状细胞的功能障碍有助于 通过驱动成人出生的异常成熟和整合，间接导致过度兴奋 DGC。我将研究 TBI 如何影响 PV+ 篮状细胞的细胞功能和 网络层面，这种功能障碍如何影响成人出生的发育和整合 DGC，以及光伏电池特定微电路结构和功能驱动是否发生变化 TBI 后整个动物癫痫发作的易感性。该提案将使用转基因小鼠 选择性地针对 PV+ 篮子细胞群来表达钙指标， 兴奋性通道视紫红质，或用于测量 PV 细胞特异性的特定合成受体 TBI 后的网络活动，以及这些细胞的功能输出。我也会 将这些技术与逆转录病毒介导的成年 DGC 标记相结合， 确定 TBI 后 PV+ 篮状细胞功能的变化是否会改变成熟， TBI 后成年 DGC 的集成或电路动力学。最后我会操纵 体内 PV+ 篮细胞的活性，以评估其在神经元回路重新布线中的作用 TBI 后，并在 TBI 后调节它们的活性，以期降低癫痫发作的易感性。 从这项研究中收集的知识将有助于指导未来的工作，从而完善我们的 使用临床了解 TBI 后受伤退伍军人的中间神经元功能障碍 数据，也许有一天能够阻止 PTE 的发展。