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: 10017359
• 负责人: SHAUN CARLSON
• 金额: $ 19.56万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017359
• 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; TBI treatment; 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.

项目概要 认知受损被认为是导致患有认知障碍的人生活质量下降的主要原因 创伤性脑损伤（TBI）。神经元通讯和正常大脑功能需要调节 神经递质释放到突触间隙。 TBI 导致多种神经递质释放受损 大脑区域，可能导致受伤后运动和认知功能障碍；然而，人们知之甚少 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) 复合物促进囊泡对接和释放 神经递质和 SNARE 复合体形成的减少与受损有关 神经传递。在 TBI 实验啮齿动物模型中，SNARE 复合体的形成减少，并且 突触小泡的分布在受伤后几周内发生改变。突触小泡糖蛋白2A (SV2A) 是易于释放的囊泡和 SNARE 复合体突触池的重要调节因子 形成。我们有初步数据表明 TBI 后突触中的 SV2A 减少。 SV2A被确定为 FDA 批准的抗癫痫药物左乙拉西坦 (Keppra) 在大脑中的结合位点。此外， 如果没有额外的比较研究，严重 TBI 指南不能推荐 Keppra。凯普拉有 少数报告显示，可促进啮齿类动物模型神经行为功能的改善 TBI，但人们对这种改进背后的机制知之甚少。我们有数据显示治疗 与 Keppra 一起使用可以改善 TBI 后 SNARE 复合体的形成。总体假设是 SV2A 发挥作用 TBI 引起的神经递质释放受损，可以通过 Keppra 治疗来恢复，以改善 神经传递。具体目标 1 将确定 TBI 对 SV2A 丰度和 SNARE 复合体的影响 谷氨酸能和 GABA 能突触前末梢的形成。具体目标 2 将决定效果 Keppra 处理对 SV2A 丰度、SNARE 复合体形成和高钾诱发的影响 TBI 后海马体中神经递质的释放。 SV2A 在介导治疗中的贡献 Keppra 的效果将在 SV2A 敲除小鼠中进行测试。该项目的成功完成将提供 对理解 TBI 后突触功能障碍以及临床潜在益处具有宝贵的见解 Keppra 在 TBI 患者中的使用。

项目成果

Assessment of behavioral, neuroinflammatory, and histological responses in a model of rat repetitive mild fluid percussion injury at 2 weeks post-injury.

• DOI: 10.3389/fneur.2022.945735
• 发表时间: 2022
• 期刊: FRONTIERS IN NEUROLOGY
• 影响因子: 3.4
• 作者: Fronczak, Katherine M.;Roberts, Andrea;Svirsky, Sarah;Parry, Madison;Holets, Erik;Henchir, Jeremy;Dixon, C. Edward;Carlson, Shaun W.
• 通讯作者: Carlson, Shaun W.