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

摘要 创伤后癫痫(PTE)可由战斗相关的创伤性脑损伤引起 (TBI)，这是一种有充分证据的现象，已导致大量神经疾病 在退伍军人中，最近与中东冲突有关(&gt；350,000例 自2000年以来与战斗有关的TBI)。不幸的是，目前对PTE的治疗是有限的 因此，许多患有PTE的退伍军人没有有效的癫痫发作控制。PTE 通常表现为一种形式的颞叶癫痫，它涉及细胞和 大脑海马区的功能回路改变。健康的人 海马齿状颗粒细胞(DGC)形成主细胞层，防止 通过较低的放电频率和相对超极化的静息产生的超兴奋性 膜电位。此外，齿状回是一个正在进行的 神经发生，在整个成年生活中产生新的DGC并整合到 现有的电路，在一个对学习和记忆至关重要的过程中。脑外伤与癫痫 涉及成年出生的DGC在海马区的异常成熟和整合， 它被认为扰乱了海马体的功能，增加了大脑的兴奋性 导致癫痫发作。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，它们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篮子细胞经历了许多功能和 网络变化，包括减少激励性输入，增加输出故障，以及 突触前钙通道功能障碍。先前的假设已经检验了这种可能性。 颅脑损伤后PV细胞功能障碍对海马区高兴奋性的直接作用。在……里面 这一提议，我假设脑外伤后PV篮子细胞的功能障碍 通过推动成人出生的异常成熟和整合，间接地导致过度兴奋 DGC。我将研究TBI如何影响光伏篮子细胞的细胞功能和 网络水平，这种功能障碍如何影响成年出生的发育和融合 DGC，以及光伏电池特有的微电路结构和功能驱动是否发生变化 颅脑损伤后全动物惊厥易感性。这项提议将使用转基因小鼠 为了选择性地将PV篮子细胞群体定位于钙指示剂的表达， 兴奋性通道视紫红质，或特定的合成受体来测量PV细胞的特异性 TBI后的网络活动，以及这些单元的功能输出。我也会 将这些技术与逆转录病毒介导的成年出生的DGC标记相结合，以 确定颅脑损伤后PV篮子细胞功能的变化是否改变成熟， 颅脑损伤后成年出生的DGC的整合或电路动力学。最后，我会操纵 活体PV篮子细胞的活性以评估它们在神经元回路重新布线中的作用 并调节其在脑损伤后的活动，以期降低癫痫的敏感性。 从这项研究中收集的知识将有助于指导未来的工作，这些工作将完善我们的 退伍军人颅脑损伤后中间神经元功能障碍的临床认识 数据，也许有一天能够阻止PTE的发展。

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.