Axonal Sprouting and Epilepsy after Traumatic CNS Injury
中枢神经系统外伤后的轴突出芽和癫痫
基本信息
- 批准号:6624509
- 负责人:
- 金额:$ 28.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2002
- 资助国家:美国
- 起止时间:2002-04-01 至 2006-03-31
- 项目状态:已结题
- 来源:
- 关键词:action potentials axon brain injury denervation electrophysiology epilepsy genetically modified animals glutamate receptor glutamates laboratory mouse laboratory rat neuronal guidance neurophysiology neurotransmitter metabolism neurotrophic factors pyramidal cells synapses trauma voltage /patch clamp
项目摘要
The Problem: Epilepsy is a common consequence of traumatic head injury. Its cause is unknown. The Hypotheses: 1) The release of neurotrophins after traumatic CNS injury triggers axonal sprouting by pyramidal cells. 2) The glutamate sensitivity and excitability of postsynaptic target cells increase as a consequence of partial denervation. 3) Injury-induced presynaptic axonal sprouting and increased postsynaptic excitability combine synergistically to cause posttraumatic epilepsy. The Model: After Schaffer collateral transection, CA3 cells in hippocampal slice cultures sprout new axon collaterals and CA1 cells become supersensitive to glutamate. These phenomena may account for the lesion-induced hyperexcitability. This model provides an experimentally tractable and informative approach for studying pre- and postsynaptic mechanisms of posttraumatic epilepsy. The genesis of hyperexcitability after axonal injury in this model will therefore be investigated using neuroanatomical, cell biological, and electrophysiological techniques. AIM 1: Determine the presynaptic mechanisms underlying injury- induced hyperexcitability. TrkB immunoadhesins, biolistic transfection with full length and dominant negative neurotrophin receptor constructs, and cultures derived from trk receptor knockout mice will be used to test the hypothesis that activation of trk receptors is required for injury-induced axonal sprouting. The hypothesis predicts that lesion-induced sprouting will not occur in the presence of trkB immunoadhesin, in cells transfected with dominant negative irk receptors or in cultures made from trk receptor knock-out mice. Lack of axonal sprouting is predicted to eliminate injury-induced hyperexcitability. AIM 2: Determine the postsynaptic mechanisms underlying injury- induced hyperexcitability. Using whole-cell voltage-clamp and laser microphotolysis of caged neurotransmitters targeted to individual distal dendrites, we will test the hypotheses that glutamate supersensitivity and intrinsic hyperexcitability occur in CA1 cells after denervation. The hypothesis predicts that changes in the levels of expression of neurotransmitter receptors and/or changes in intrinsic voltage-dependent ionic conductances underlie the potentiation of dendritic glutamate responses observed previously after Schaffer collateral transection. The Goal: to better understand the causes of posttraumatic epilepsy and, ultimately, to offer new and improved prophylactic therapeutic strategies to cure this disease.
问题:癫痫是创伤性头部损伤的常见后果。 其原因尚不清楚。假设:1)中枢神经系统损伤后神经营养因子的释放触发锥体细胞轴突发芽。2)谷氨酸敏感性和兴奋性的突触后靶细胞增加的结果部分去神经。3)损伤诱导的突触前轴突发芽和突触后兴奋性增加联合收割机协同作用导致创伤后癫痫。模型:切断侧支后,海马脑片培养的CA 3细胞长出新的轴突侧支,CA 1细胞对谷氨酸超敏感。 这些现象可以解释病变引起的过度兴奋。 该模型为研究创伤后癫痫的突触前和突触后机制提供了一种实验上易处理和信息丰富的方法。 因此,将使用神经解剖学、细胞生物学和电生理学技术研究该模型中轴突损伤后的过度兴奋的起源。目的1:确定损伤诱导的过度兴奋的突触前机制. TrkB免疫粘附素、用全长和显性负性神经营养因子受体构建体进行的生物射弹转染、以及源自trk受体敲除小鼠的培养物将用于检验以下假设:损伤诱导的轴突发芽需要激活trk受体。该假说预测,在存在trkB免疫粘附素的情况下,在用显性负性irk受体转染的细胞中或在由trk受体敲除小鼠制成的培养物中不会发生损伤诱导的发芽。 预测轴突发芽的缺乏消除损伤诱导的过度兴奋。目的2:探讨损伤性兴奋的突触后机制. 使用全细胞电压钳和激光显微光解的笼状神经递质针对个别远端树突,我们将测试的假设,谷氨酸超敏感性和内在的超兴奋性发生在CA 1细胞失神经支配后。 该假说预测,神经递质受体的表达水平的变化和/或内在的电压依赖性离子电导的变化的基础上观察到的增强树突状谷氨酸反应后,谢弗侧支横断。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这种疾病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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SCOTT M. THOMPSON其他文献
SCOTT M. THOMPSON的其他文献
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{{ truncateString('SCOTT M. THOMPSON', 18)}}的其他基金
Stress, depression and effects of novel antidepressants on excitatory synapses
压力、抑郁和新型抗抑郁药对兴奋性突触的影响
- 批准号:
9270600 - 财政年份:2010
- 资助金额:
$ 28.22万 - 项目类别:
Central Pain Syndrome: Thalamic Hyperexcitability After Denervation?
中枢性疼痛综合征:去神经后丘脑过度兴奋?
- 批准号:
7369672 - 财政年份:2007
- 资助金额:
$ 28.22万 - 项目类别:
Central Pain Syndrome: Thalamic Hyperexcitability After Denervation?
中枢性疼痛综合征:去神经后丘脑过度兴奋?
- 批准号:
7254559 - 财政年份:2007
- 资助金额:
$ 28.22万 - 项目类别:
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:
7991811 - 财政年份:2002
- 资助金额:
$ 28.22万 - 项目类别:
Axonal Sprouting and Epilepsy after Traumatic CNS Injury
中枢神经系统外伤后的轴突出芽和癫痫
- 批准号:
6875711 - 财政年份:2002
- 资助金额:
$ 28.22万 - 项目类别:
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 - 财政年份:2002
- 资助金额:
$ 28.22万 - 项目类别:
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