Lithium as a Therapeutic Approach to Attenuate Synaptic Deficits after TBI

 描述（由申请人提供）：TBI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。尽管在理解创伤性脑损伤（TBI）的多方面病理生物学方面取得了进展，但在临床上还没有治疗剂被批准用于治疗TBI。 审判本实验室以前的工作表明，海马乙酰胆碱释放的缺陷有助于损伤后神经行为功能障碍的表现，但很少 神经传递受损的潜在机制在未受伤的大脑中，N-乙基马来酰亚胺敏感因子附着蛋白受体（SNARE）复合物的形成促进囊泡对接和神经递质释放;然而，尚未研究TBI对SNARE复合物的影响。我们推测SNARE复合体和突触囊泡分布的改变有助于TBI后神经传递受损和行为功能障碍。拟议的工作将测试锂在减轻突触内损伤，促进突触可塑性和细胞存活以及改善TBI后神经行为功能方面的功效。为此，我们将利用大鼠和小鼠TBI模型来检查锂的治疗能力。此外，我们将使用市售的半胱氨酸串蛋白α（CSPa）基因敲除小鼠研究锂在突触中作用的特异性。在目标1中，我们将评估锂对TBI后多个时间点的SNARE蛋白丰度和复合物形成的影响。此外，我们将通过透射电子显微镜和微透析分别研究锂对TBI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TBI后数周内突触可塑性、海马神经元存活和神经行为功能的影响。拟议的工作将提供TBI后突触囊泡分布变化和SNARE复合体改变的首次评估。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以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.