Pre and Postsynaptic Consequences of Traumatic CNS Injury

描述（由申请方提供）：创伤性CNS损伤引起几种神经系统疾病，其特征为兴奋性延迟增加，如创伤后癫痫，机制未知。在这个建议中，我们专注于两个基本的前和突触后后果的创伤性损伤，可能占在这些条件下的超兴奋性：轴突损伤和神经元群体的去神经支配。假设：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出芽，以及2）切断的轴突的变性触发部分去神经细胞的内在突触后兴奋性增加。如果是这样的话，那么阻止轴突发芽和恢复突触后兴奋性将减轻损伤诱导的过度兴奋，并为创伤后癫痫提供有用的治疗方法。模型：我们将在大鼠和基因改变小鼠的穿透性CNS损伤模型中测试这些假设。将在离体海马脑片和海马脑片培养物中对创伤后癫痫进行电生理学和形态学研究，因为轴突损伤和神经元去神经支配可以在空间上分别局限于CA3和CA1区域，因此在横断Schaffer侧支通路后的不同时间进行海马脑片培养。目的1：确定突触前轴突发芽作为损伤诱导的过度兴奋的海马在体外和体内的作用。其中trkB神经营养因子受体已被修饰以使其对药理学阻断敏感的小鼠将被用于测试以下假设：轴突发芽和过度兴奋需要trkB受体的激活。目的2：探讨海马损伤后过度兴奋的突触后机制。我们将测试的假设，谷氨酸超敏感性和增加的内在超兴奋性发生在CA1锥体细胞失神经支配后。目标：为了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。 项目叙述：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.