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 认知功能受损被认为是导致患有糖尿病的个体生活质量下降的主要因素。 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。TBI导致多种神经递质释放受损 大脑区域，并可能导致运动和认知功能障碍的伤害;然而，知之甚少， 造成这种损伤的机制。高度保守的N-乙基马来酰亚胺- 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复合物形成的减少与受损的 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， 突触囊泡的分布在损伤后的几周内改变。突触囊泡糖蛋白2A （SV 2A）是一个重要的调节突触池的易释放囊泡和陷阱复合物 阵我们有初步数据表明，SV 2A在TBI后突触中减少。SV 2A被鉴定为 FDA批准的抗癫痫药物左乙拉西坦（Keppra）在大脑中的结合位点。而且 严重TBI指南不能推荐Keppra，除非进行额外的比较研究。凯普拉已经 在少数报告中显示，在啮齿动物模型中， TBI，但这种改善的机制知之甚少。我们有数据显示 Keppra可改善TBI后SNARE复合物的形成。总的假设是SV 2A发挥作用 在TBI诱导的受损神经递质释放，这可以恢复与治疗Keppra，以改善 神经传递具体目标1将确定TBI对SV 2A丰度和SNARE复合物的影响 突触前末梢中的谷氨酸能和GABA能的形成。具体目标2将决定 Keppra治疗对SV 2A丰度、SNARE复合物形成和高钾诱发的 脑外伤后海马神经递质的释放。SV 2A在介导抗肿瘤治疗中的作用 将在SV 2A敲除小鼠中测试Keppra的作用。该项目的成功完成将提供 了解TBI后突触功能障碍的有价值的见解和临床应用的潜在益处 Keppra在TBI患者中的应用