SNARE Proteins and TBI

描述（由申请人提供）：创伤性脑损伤（TBI）会导致认知、行为、情绪和身体功能的紊乱。正常的大脑认知功能依赖于通过神经递质释放的突触通讯。脑外伤可导致多巴胺能和胆碱能诱发的神经递质释放持续不足，但机制尚不清楚。神经递质在突触的释放需要突触囊泡与突触前质膜的融合。这个过程的关键步骤包括可溶性n -乙基丙烯酰亚胺敏感因子附着蛋白受体（SNARE）复合物的组装，这是一个高度稳定的平行四螺旋束，形成于突触囊泡SNARE synaptobrevin 2 （syb2）和质膜SNAREs syntaxin 1和突触体相关蛋白25 kDa （SNAP-25）之间。SNARE蛋白的病理可能在TBI中起重要作用，特别是在神经传递和随后的认知障碍方面。半胱氨酸弦蛋白α （CSP¿）在突触活动期间通过陪伴SNAP-25促进snare复合物组装。最近发现，在治疗相关浓度下，锂可以增强CSP¿的表达。这代表了一种新的机制，通过锂可以恢复脑外伤后神经递质释放缺陷。为了进一步评估CSP¿在介导锂对脑外伤后SNARE蛋白和认知恢复的影响中的作用，本项目将在CSP¿转基因小鼠中评估锂治疗。本研究的目的是研究脑外伤后神经传递缺陷的复杂机制。总的假设是，脑外伤后的认知缺陷可能至少部分归因于突触snare复合物形成的损伤和随后的神经递质释放缺陷。特异性目标1将检查TBI对单个SNARE蛋白、SNARE复合物组装和CSP¿（SNARE复合物组装的关键调节因子）的影响。特异性目标2将确定锂是否增加CSP¿的表达与snare复合物组装的恢复和微透析测量的诱发神经递质释放有关。具体目标3将确定锂是否可以减轻脑外伤后的认知缺陷。该项目的成功完成可能会提供证据，证明创伤性脑损伤后snare复合物会减少，并确定锂在创伤后认知缺陷治疗中的新应用。

DESCRIPTION (provided by applicant): Traumatic Brain Injury (TBI) can result in the disturbance of cognitive, behavioral, emotional, and physical functioning. Normal brain cognitive function depends on synaptic communication via neurotransmitter release. TBI can produce persistent deficits in both dopaminergic and cholinergic evoked neurotransmitter release, but the mechanisms are unknown. Neurotransmitter release at the synapse requires fusion of synaptic vesicles with the presynaptic plasma membrane. A crucial step in this process involves the assembly of a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, a highly stable, parallel four-helix bundle formed between the synaptic vesicle SNARE synaptobrevin 2 (syb2) and the plasma membrane SNAREs syntaxin 1 and synaptosome-associated protein of 25 kDa (SNAP-25). The pathology of SNARE proteins may play an important role in TBI, especially concerning neurotransmission and subsequent cognitive disturbances. Cysteine string protein alpha (CSP¿) promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity. It has recently been discovered that lithium, at therapeutically relevant concentrations, can enhance the expression of CSP¿. This represents a novel mechanism by which lithium may restore neurotransmitter release deficits after TBI. To further evaluate the role of CSP¿ in mediating lithium's effect on SNARE proteins and cognitive recovery after TBI, this project will evaluate lithium therapy in a CSP¿ transgenic mouse. The goal of this proposal is to examine SNARE-complex mechanisms of neurotransmission deficits after TBI. The overall hypothesis is that cognitive deficits following TBI may be, at least partialy, attributable to impairment in synaptic SNARE-complex formation and subsequent neurotransmitter release deficits. Specific Aim 1 will examine the effects of TBI on individual SNARE proteins, SNARE- complex assembly, and CSP¿, a key regulator of SNARE-complex assembly. Specific Aim 2 will determine if increasing the expression of CSP¿ by lithium is associated with a restoration of SNARE-complex assembly and evoked neurotransmitter release as measured by microdialysis. Specific Aim 3 will determine if lithium can attenuate cognitive deficits after TBI. Successful completion of this project may provide evidence that SNARE-complexes are diminished after TBI and identify a novel application of lithium for the treatment of posttraumatic cognitive deficits. PUBLIC HEALTH RELEVANCE: Approximately 1.7 million people sustain traumatic brain injury (TBI) each year in the United States and more than 5.3 million people live with disabilities caused by TBI. In this study, we will investigate a new mechanism of cognitive post-traumatic cognitive deficits and will evaluate lithium therapy as a countermeasure. If successful, this study would lead to the development of a new use for an FDA-approved drug for the treatment of memory deficits after TBI.