Pre and Postsynaptic Consequences of Traumatic CNS Injury

描述(申请人提供)：创伤性中枢神经系统损伤导致几种神经紊乱，其特点是兴奋性延迟增加，如创伤后癫痫，机制不明。在这项研究中，我们将重点放在创伤性损伤的突触前和突触后的两个基本后果上，这两个后果可能解释了在这些情况下的过度兴奋：轴突损伤和神经元群体的失神经。假说：穿透性损伤后神经元兴奋性增加，因为1)神经营养因子的释放触发突触前轴突萌发，2)切断的轴突变性触发部分失神经细胞固有的突触后兴奋性增加。如果是这样的话，防止轴突发芽和恢复突触后兴奋性将减轻损伤引起的过度兴奋性，并为创伤后癫痫提供有用的治疗方法。模型：我们将在大鼠和转基因小鼠的中枢神经系统穿透性损伤模型中测试这些假说。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，因此，在切断Schaffer侧支通路后的不同时间，将在体外海马片和海马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：在体内外研究突触前轴突萌发在损伤诱导的海马区高兴奋性中的作用。在TrkB神经营养素受体已被修饰以使其对药物阻断敏感的小鼠中，将被用来检验这样的假设，即TrkB受体的激活是轴突萌芽和过度兴奋所必需的。目的2：探讨海马区损伤后高兴奋性的突触后机制。我们将验证在去神经支配后CA1锥体细胞发生谷氨酸超敏和内源性超兴奋性增加的假说。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来治愈或预防这些疾病。 项目简介：我们寻求发现严重头部损伤后癫痫形式的原因，并开发新的治疗方法来治疗或预防这种情况。

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.