Chronic Lithium Therapy for Traumatic Brain Injury

描述(由申请人提供)： 部署在阿富汗战争(持久自由行动；OEF)和伊拉克战争(伊拉克自由行动；OIF)的军事人员因暴露于爆炸(即爆炸产生的冲击波)和其他类型的头部损伤而遭受创伤性脑损伤的风险很高(12，52)。虽然早期干预对于钝化继发性损伤和最大限度地提高功能结果很重要，但退伍军人也需要长期干预，以帮助恢复因脑外伤而导致的持续衰弱症状。虽然运动功能有显著改善的趋势，但残存的认知障碍仍然是各种严重脑外伤患者最关心的问题。正常的大脑认知功能依赖于通过神经递质释放的突触交流。我们先前已经证明，实验性脑外伤可以在诱发的神经递质释放方面产生持续性缺陷，但机制尚不清楚。突触的神经递质释放需要突触小泡与突触前质膜的融合。在这个过程中的一个关键步骤是组装一个可溶的N-乙基马来酰亚胺敏感因子附着蛋白受体(SNARE)复合体，它是一个高度稳定的、平行的四螺旋束，形成于突触小泡SNARE Synaptobrevin 2(SYB2)和质膜SNARS Synaxin 1和25 kDa突触体相关蛋白(SNAP-25)之间。SNARE蛋白的病理可能在脑损伤中起重要作用，特别是在神经传递和随后的认知障碍方面。半胱氨酸串蛋白α(CSP)在突触活动过程中通过陪伴SNAP-25促进SNARE-复合体的组装。最近发现，锂在治疗上具有相关性 浓度越大，CSP的表达越强。这代表了一种新的机制，锂可以通过它来恢复脑损伤后神经递质释放的缺陷。我们有初步证据表明，经锂盐治疗后，脑外伤后CSP？表达和SNARE-Complex组装均减少。众所周知，锂有多种作用。我们 还将把锂处理对SNARE蛋白的慢性影响与代表锂的传统作用机制的GSK3b和BDNF水平进行对比。这项建议的目的是确定慢性脑外伤对神经传递的关键陷阱-复杂机制的影响。总的假设是，脑外伤后的慢性认知障碍可能至少部分归因于突触陷阱复合体的形成障碍和随后的神经递质释放障碍。具体目标1将研究TBI对单个SNARE蛋白、SNARE-复合体组装和SNARE-复合体组装的关键调节因子CSP的影响。具体目标2将确定锂盐增加CSP的表达是否与SNARE-Complex组装、认知功能和组织病理学的恢复有关。具体目标3将确定锂在减轻SNARE复合体丢失的剂量下，是否可以减轻脑外伤后诱发的神经递质释放缺陷。锂治疗是以慢性间隔开始的，这与退伍军人暴露于脑外伤诱发的体力有关。这一项目的成功完成可能提供证据表明，颅脑损伤后诱捕复合体和认知功能慢性减弱，并可以至少部分恢复 锂盐疗法。

DESCRIPTION (provided by applicant): Military personnel deployed to the wars in Afghanistan (Operation Enduring Freedom; OEF) and Iraq (Operation Iraqi Freedom; OIF) are at high risk of sustaining a traumatic brain injury (TBI) from exposures to a blast (i.e., blast waves from explosions) and other types of head injuries (12,52). While early interventions are important to blunt secondary injury and maximize functional outcome, chronic interventions are also needed by veterans to aid recovery of persistent debilitating symptoms resulting from TBI. While motor functions tend to improve significantly, residual cognitive disturbance remains the most significant concern of persons with all severities of TBI. Normal brain cognitive function depends on synaptic communication via neurotransmitter release. We have previously shown that experimental TBI can produce persistent deficits in 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. We have preliminary evidence showing a decrease in both CSP¿ expression and SNARE-complex assembly after TBI that is attenuated by lithium treatment. It is well known that lithium has multiple actions. We will also contrast the chronic effects of lithium treatment on SNARE proteins to GSK3b and BDNF levels which represent traditional mechanisms of action of lithium. The goal of this proposal is to determine the effects of chronic TBI on key SNARE-complex mechanisms of neurotransmission. The overall hypothesis is that chronic cognitive deficits following TBI may be, at least partially, 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, cognitive function, and histopathology. Specific Aim 3 will determine if lithium, at doses that attenuate SNARE complex loss, can attenuate evoked neurotransmitter release deficits after TBI. Lithium treatment is initiated at chronic intervals that are relevant to Veteran's exposed to TBI-inducing physical forces. Successful completion of this project may provide evidence that SNARE-complexes and cognitive function are chronically diminished after TBI and can be restored, at least partially, by lithium therapy.