SV2A as a Therapeutic Target for Improved Neurotransmission after Traumatic Brain Injury

项目摘要 认知障碍被认为是导致阿尔茨海默病患者生活质量下降的主要原因 创伤性脑损伤(TBI)。神经元通讯和正常的大脑功能需要调节 神经递质释放到突触间隙。脑外伤导致多发性脑损伤患者神经递质释放受损 脑区和损伤后的运动和认知功能障碍；然而，知之甚少 关于造成这种损害的机制。高度保守的N-乙基马来酰亚胺的形成 敏感因子附着蛋白受体(SNARE)复合体促进囊泡对接和释放 神经递质和圈套复合体形成的减少与受损有关 神经传递。在实验性脑创伤啮齿动物模型中，诱捕复合体的形成减少， 在损伤后的几周内，突触小泡的分布发生了变化。突触小泡糖蛋白2A (SV2A)是易释放的囊泡和圈套复合体的突触池的重要调节者 队形。我们有初步数据表明，脑损伤后突触中的SV2a减少。SV2a被确认为 FDA批准的抗癫痫药物左乙拉西坦(Keppra)在大脑中的结合部位。此外， 如果没有额外的比较研究，重型颅脑损伤指南不能推荐凯普拉。凯普拉有 在少数报告中显示了促进改善啮齿动物模型的神经行为功能 但这种改善背后的机制还知之甚少。我们有数据显示治疗 凯普拉可改善颅脑损伤后圈套复合体的形成。总的假设是SV2a起作用 在脑外伤后神经递质释放受损的情况下，经凯普拉治疗后可恢复 神经传递。具体目标1将确定脑损伤对SV2A丰度和圈套复合体的影响 谷氨酸能和GABA能突触前终末的形成。具体目标2将决定 凯普拉对SV2a丰度、圈套复合体形成和高钾诱发的影响 脑外伤后海马区神经递质的释放。SV2a在介导治疗中的作用 凯普拉的作用将在SV2A基因敲除小鼠身上进行测试。该项目的成功完成将提供 对理解脑外伤后突触功能障碍的有价值的见解及其对临床的潜在益处 凯普拉在颅脑损伤患者中的应用

Project Summary Impaired cognition is named as a major contributor to reduced quality of life in individuals living with a traumatic brain injury (TBI). Neuronal communication and normal brain function require regulated neurotransmitter release into the synaptic cleft. TBI results in impaired neurotransmitter release in multiple brain regions and can contribute to motor and cognitive dysfunction following injury; however, little is known about the mechanisms contributing to this impairment. Formation of the highly-conserved N-ethylmaleimide- sensitive factor attachment protein receptor (SNARE) complex facilitates vesicular docking and release of neurotransmitters, and reductions in SNARE complex formation are associated with impaired neurotransmission. In experimental rodent models of TBI, SNARE complex formation is reduced and the distribution of synaptic vesicles are altered in the weeks following injury. The synaptic vesicle glycoprotein 2A (SV2A) is an important regulator of the synaptic pool of readily releasable vesicles and SNARE complex formation. We have preliminary data that SV2A is reduced in synapses after TBI. SV2A was identified as the binding site of the FDA approved antiepileptic drug Levetiracetam (Keppra) in the brain. Furthermore, the Guidelines for Severe TBI cannot recommend Keppra without additional comparative studies. Keppra has been shown in a small number of reports to promote improved neurobehavioral function in rodent models of TBI, but the mechanism underlying this improvement is poorly understood. We have data showing treatment with Keppra can improve SNARE complex formation after TBI. The overall hypothesis is that SV2A plays a role in TBI-induced impaired neurotransmitter release, which can be restored with treatment of Keppra to improve neurotransmission. Specific Aim 1 will determine the effect of TBI on SV2A abundance and SNARE complex formation in glutamatergic and GABAergic pre-synaptic terminals. Specific Aim 2 will determine the effect of Keppra treatment on SV2A abundance, SNARE complex formation, and high-potassium evoked neurotransmitter release in the hippocampus after TBI. The contribution of SV2A in mediating the therapeutic effects of Keppra will be tested in SV2A knockout mice. Successful completion of this project will provide valuable insights into the understanding of synaptic dysfunction after TBI and potential benefits for clinical usage of Keppra in TBI patients.