Pre and Postsynaptic Consequences of Traumatic CNS Injury

中枢神经系统损伤的突触前和突触后后果

• 批准号: 7383287
• 负责人: SCOTT M. THOMPSON
• 金额: $ 32.81万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7383287
• 关键词: Accounting; Area; Axon; Biological; Calcium-Activated Potassium Channel; Cells; Condition; Craniocerebral Trauma; Deafferentation procedure; Denervation; Epilepsy; Glutamates; Goals; Hippocampus (Brain); In Vitro; Injury; Lasers; Lesion; Modeling; Mus; Nerve Growth Factor Receptors; Neuronal Injury; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Pathway interactions; Population; Pyramidal Cells; Rattus; Role; Slice; Techniques; Testing; Therapeutic; Time; Traumatic Brain Injury; Traumatic CNS injury; axonal sprouting; central nervous system injury; improved; in vivo; nervous system disorder; neuronal excitability; neurotrophic factor; postsynaptic; presynaptic; prevent; prophylactic; voltage clamp

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.

描述（由申请人提供）：创伤性中枢神经系统损伤会导致多种神经系统疾病，其特征是兴奋性延迟增加，例如创伤后癫痫，其机制未知。在本提案中，我们重点关注创伤性损伤的两个基本的突触前和突触后后果，这可能是这些情况下过度兴奋的原因：轴突损伤和神经元群的去神经支配。假设：穿透性损伤后神经元兴奋性增加，因为 1) 神经营养素的释放触发突触前轴突萌芽，2) 切断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，那么防止轴突出芽和恢复突触后兴奋性将减轻损伤引起的过度兴奋，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造小鼠的穿透性中枢神经系统损伤模型中测试这些假设。外伤后癫痫将在离体海马切片和横断 Schaffer 侧支通路后不同时间的海马切片培养物中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可以分别在空间上限制在 CA3 和 CA1 区域。目标 1：确定突触前轴突萌芽作为损伤引起的海马体外和体内过度兴奋的原因的作用。 trkB 神经营养蛋白受体已被修饰以使其对药理学阻断敏感的小鼠将用于测试轴突萌芽和过度兴奋需要激活 trkB 受体的假设。目标 2：确定损伤引起的海马过度兴奋的突触后机制。我们将测试去神经后 CA1 锥体细胞中出现谷氨酸超敏感性和内在过度兴奋性增加的假设。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来治愈或预防这些疾病。 项目叙述：我们寻求发现严重头部受伤后发生癫痫形式的原因，并开发新的疗法来治疗或预防这种情况。