Pre and Postsynaptic Consequences of Traumatic CNS Injury

描述（由申请人提供）：外伤性中枢神经系统损伤导致几种神经系统疾病，其特征是兴奋性延迟增加，如创伤后癫痫，机制未知。在这一建议中，我们集中在两个基本的创伤性损伤的突触前和突触后的后果，可能解释在这些条件下的高兴奋性：轴突损伤和神经群的去神经支配。假设：穿透性损伤后神经元兴奋性增加的原因是：1)神经营养物质的释放触发突触前轴突发芽；2)被切断的轴突变性触发部分失神经细胞内在的突触后兴奋性增加。如果是这样，那么防止轴突发芽和恢复突触后兴奋性将减轻损伤性高兴奋性，为创伤后癫痫的治疗提供有用的方法。模型：我们将在大鼠和转基因小鼠穿透性中枢神经系统损伤模型中验证这些假设。由于轴突损伤和神经元失神经在空间上分别局限于CA3和CA1区域，因此将在舍弗侧支通路横断后的不同时间，在离体海马切片和海马切片培养中对创伤后癫痫进行电生理学和形态学研究。目的1：确定突触前轴突发芽在体外和体内海马损伤性高兴奋性中的作用。trkB神经营养因子受体经过修饰，使其对药物阻断敏感的小鼠将被用于验证trkB受体的激活是轴突发芽和高兴奋性所必需的假设。目的2：确定海马损伤诱导的高兴奋性的突触后机制。我们将检验在去神经支配后CA1锥体细胞中发生谷氨酸超敏感和内在高兴奋性增加的假设。目标：更好地了解创伤后癫痫的原因，并最终提供新的和改进的预防性治疗策略，以治愈或预防这些疾病。

DESCRIPTION (provided by applicant): Traumatic CNS injury causes several neurological disorders that are characterized by a delayed increase in excitability, such as posttraumatic epilepsy, by unknown mechanisms. In this proposal, we focus on two fundamental pre- and postsynaptic consequences of traumatic injury that may account for hyperexcitability in these conditions: axonal injury and denervation of neuronal populations. The Hypotheses: Neuronal excitability is increased after a penetrating injury because 1) the release of neurotrophins triggers presynaptic axonal sprouting, and 2) degeneration of severed axons triggers an increase in the intrinsic postsynaptic excitability of partially denervated cells. If so, then preventing axonal sprouting and restoring postsynaptic excitability will alleviate injury- induced hyperexcitability and provide useful therapeutic approaches for posttraumatic epilepsy. The Model: We will test these hypotheses in a model of penetrating CNS injury in rats and genetically altered mice. Posttraumatic epilepsy will be studied electrophysiologically and morphologically in ex vivo hippocampal slices and in hippocampal slice cultures at various times after making a transection of the Schaffer collateral pathway because axonal injury and neuronal denervation can be spatially confined to the CA3 and CA1 regions, respectively. AIM 1: Determine the role of presynaptic axonal sprouting as a cause of injury-induced hyperexcitability in the hippocampus in vitro and in vivo. Mice in which the trkB neurotrophin receptor has been modified to render it sensitive to pharmacological blockade will be used to test the hypothesis that activation of trkB receptors is required for axonal sprouting and hyperexcitability. AIM 2: Determine the postsynaptic mechanisms underlying injury-induced hyperexcitability in the hippocampus. We will test the hypotheses that glutamate supersensitivity and increased intrinsic hyperexcitability occur in CA1 pyramidal cells after denervation. The Goal: To better understand the causes of posttraumatic epilepsy and, ultimately, to offer new and improved prophylactic therapeutic strategies to cure or prevent these conditions. Project Narrative: We seek to discover the causes of the form of epilepsy that occurs after a severe head injury and to develop new therapies to treat or prevent this condition.