Lithium as a Therapeutic Approach to Attenuate Synaptic Deficits after TBI

 描述(由申请人提供)：脑损伤产生复杂的病理生理学，导致进行性细胞功能障碍和死亡，最终导致运动和认知能力受损。尽管对创伤性脑损伤的多方面病理生物学研究取得了进展，但临床上尚无治疗方法被批准。 审判。我们实验室以前的工作表明，海马区乙酰胆碱释放不足有助于损伤后神经行为功能障碍的表现，但作用很小 已知神经传递受损的潜在机制。在未受损伤的脑中，N-乙基马来酰亚胺敏感因子附着蛋白受体(SNARE)复合体的形成促进了囊泡对接和神经递质的释放；然而，TBI对SNARE复合体的影响尚未被研究。我们推测，颅脑损伤后SNARE复合体和突触小泡分布的改变导致神经传递受损和行为功能障碍。这项拟议的工作将测试锂在减轻脑外伤后突触内损伤、促进突触可塑性和细胞存活以及改善神经行为功能方面的有效性。为此，我们将利用大鼠和小鼠的脑外伤模型来检测锂的治疗能力。此外，我们将使用商业上可用的半胱氨酸串蛋白α(CSPA)基因敲除小鼠来检查锂在突触中作用的特异性。在目标1中，我们将评估锂对颅脑损伤后多个时间点SNARE蛋白丰度和复合体形成的影响。此外，我们还将通过透射电子显微镜和微透析法分别检测锂对脑损伤后突触囊泡分布和密度以及神经递质释放的影响。在目标2中，我们将研究锂对脑损伤后几周内突触可塑性、海马神经元存活和神经行为功能的影响。这项拟议的工作将首次评估脑损伤后突触小泡分布的变化和SNARE复合体的变化。这项工作的成功完成将为我们理解突触功能障碍和开发基于锂的方法来促进受损大脑的恢复提供有价值的见解。

 DESCRIPTION (provided by applicant): A TBI produces complex pathophysiology contributing to progressive cellular dysfunction and death that can culminate in impaired motor and cognitive abilities. Despite advances in understanding the multifaceted pathobiology of traumatic brain injury (TBI), no therapeutic has been approved for the treatment of TBI in clinical trials. Previous work from our lab demonstrates that deficits in acetylcholine release in the hippocampus contribute to the manifestation of neurobehavioral dysfunction after injury, but little is known about the mechanisms underlying impaired neurotransmission. In the uninjured brain, the formation of the N- ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex facilitates vesicular docking and neurotransmitter release; however, the effects of TBI on the SNARE complex have not been examined. We hypothesize that alterations in the SNARE complex and synaptic vesicle distribution contribute to impaired neurotransmission and behavioral dysfunction after TBI. The proposed work will test the efficacy of lithium to attenuate intrasynaptic impairments, promote synaptic plasticity and cell survival, and improve neurobehavioral function after TBI. To this end, we will utilize rat and mouse models of TBI to examine the therapeutic capacity of lithium. Additionally, we will examine the specificity of lithium's action in the synapse using commercially available cysteine string protein alpha (CSPa) knockout mice. In Aim 1, we will evaluate the effect of lithium on SNARE protein abundance and complex formation at multiple time points after TBI. Additionally, we will examine the effect of lithium on synaptic vesicular distribution and density and neurotransmitter release after TBI by transmission electron microscopy and microdialysis, respectively. In Aim 2, we will examine the effect of lithium on synaptic plasticity, hippocampal neuron survival, and neurobehavioral function in the weeks following TBI. The proposed work will provide the first evaluation of changes in synaptic vesicle distribution and alterations in the SNARE complex after TBI. Successful completion of this work will provide valuable insights into our understanding of synaptic dysfunction and the development of lithium based approaches to promote recovery in the injured brain.