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

SV2A 作为改善脑外伤后神经传递的治疗靶点

• 批准号: 9893546
• 负责人: SHAUN CARLSON
• 金额: $ 23.48万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893546
• 关键词: Adult; Antiepileptic Agents; Attention; Binding; Binding Sites; Brain; Brain region; Calcium; Child; Clinical; Communication; Comparative Study; Complex; Control Groups; Data; Docking; FDA approved; Fluorescence; Functional disorder; Glutamates; Glycoproteins; Guidelines; Hippocampus (Brain); Impaired cognition; Impairment; Individual; Injury; Keppra; Knock-out; Knockout Mice; Lateral; Learning; Levetiracetam; Measurement; Mediating; Memory; Modeling; Motor; N-ethylmaleimide-sensitive protein; Names; Nerve Degeneration; Neurons; Neurotransmitters; Pathology; Patients; Play; Potassium; Presynaptic Terminals; Process Assessment; Prophylactic treatment; Proteins; Quality of life; Recommendation; Regimen; Reporting; Rodent Model; Role; SNAP receptor; Seizures; Sorting - Cell Movement; Specificity; Synapses; Synaptic Cleft; Synaptic Vesicles; Synaptosomes; Testing; Therapeutic; Therapeutic Effect; Traumatic Brain Injury; Vesicle; Work; cognitive function; fluid percussion injury; gamma-Aminobutyric Acid; hippocampal subregions; improved; improved functioning; insight; motor disorder; neurobehavioral; neurotransmission; neurotransmitter release; novel; presynaptic; receptor; synaptic function; therapeutic target; valproate; vesicular release

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.

项目摘要 认知受损被称为降低患者生活质量的主要贡献者 创伤性脑损伤（TBI）。神经元通信和正常的大脑功能需要调节 神经递质释放到突触裂缝中。 TBI导致多个神经递质释放受损 受伤后的大脑区域，可能导致运动和认知功能障碍；但是，鲜为人知 关于导致这种损害的机制。形成高度保存的N-乙基马来酰亚胺 - 敏感因子附着蛋白受体（SNARE）复合物有助于囊泡对接和释放 神经递质和SNARE复合物形成的减少与受损相关 神经传递。在TBI的实验啮齿动物模型中，SNARE复合物的形成减少了，并 突触囊泡的分布在受伤后的几周内改变。突触囊泡糖蛋白2a （SV2A）是易于释放的囊泡的突触库的重要调节剂 形成。我们有初步的数据，即TBI之后的突触中SV2A减少了。 SV2A被确定为 FDA的结合位点批准了大脑中的抗癫痫药左旋核酸酯（Keppra）。此外， 如果没有其他比较研究，严重TBI的指南就不能推荐凯普拉。凯普拉有 在少数报告中显示，以促进改善的神经行为功能 TBI，但是这种改进的机制知之甚少。我们有显示治疗的数据 使用Keppra可以改善TBI之后的军鼓复合物的形成。总体假设是SV2A起作用 在TBI引起的神经递质释放受损中，可以通过keppra的处理来恢复以改进 神经传递。具体目标1将确定TBI对SV2A丰度和圈套综合体的影响 谷氨酸能和GABA能前突触前末端的形成。具体目标2将决定 SV2A丰度，圈套复合物的形成和高钾象的keppra处理 TBI后，神经递质在海马中释放。 SV2A在介导治疗方面的贡献 Keppra的影响将在SV2A敲除小鼠中进行测试。该项目的成功完成将提供 对TBI后突触功能障碍的理解的宝贵见解和临床的潜在益处 在TBI患者中使用Keppra。