Lithium as a Therapeutic Approach to Attenuate Synaptic Deficits after TBI

锂作为减轻 TBI 后突触缺陷的治疗方法

• 批准号: 9177697
• 负责人: SHAUN CARLSON
• 金额: $ 5.8万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2017-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9177697
• 关键词: Acetylcholine; Acute; Attenuated; Behavioral; Biological Assay; Brain; Brain Injuries; Brain region; Calcium; Cell Survival; Cessation of life; Clinical Trials; Complex; Data; Dendritic Spines; Development; Docking; Evaluation; Functional disorder; Glutamates; High Pressure Liquid Chromatography; Hippocampus (Brain); Histology; Hour; Immunoblotting; Impaired cognition; Impairment; Injury; Knockout Mice; Learning; Left; Lithium; Mediating; Membrane; Memory; Microdialysis; Molecular Chaperones; Morphology; Motor; N-ethylmaleimide-sensitive protein; Names; Neurobehavioral Manifestations; Neurons; Neurotransmitters; Pathology; Patients; Phase; Physiologic Monitoring; Polymerase Chain Reaction; Property; Proteins; Quality of life; Rattus; Recovery; Recovery of Function; Research Project Grants; Role; S-nitro-N-acetylpenicillamine; SNAP receptor; Specificity; Survivors; Synapses; Synaptic Cleft; Synaptic Membranes; Synaptic Vesicles; Synaptic plasticity; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Three-dimensional analysis; Time; Transmission Electron Microscopy; Traumatic Brain Injury; Traumatic Brain Injury recovery; VAMP-2; Work; alpha synuclein; base; cognitive ability; cysteine string protein; density; efficacy testing; gamma-Aminobutyric Acid; improved; insight; motor disorder; mouse model; neurobehavioral; neurotransmission; neurotransmitter release; novel; presynaptic; public health relevance; receptor; reconstruction; synaptic function; syntaxin

 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.

 描述（由申请人提供）：TBI 会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 (TBI) 的多方面病理学的了解取得了进展，但临床上尚未批准用于治疗 TBI 的治疗方法 试验。我们实验室之前的工作表明，海马乙酰胆碱释放的缺陷导致损伤后神经行为功能障碍的表现，但很少 已知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）复合物的形成促进了囊泡对接和神经递质释放；然而，TBI 对 SNARE 复合体的影响尚未得到研究。我们假设 SNARE 复合体和突触小泡分布的改变导致 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) 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 TBI 后多个时间点锂对 SNARE 蛋白丰度和复合物形成的影响。此外，我们将分别通过透射电子显微镜和微透析检查锂对 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，我们将研究锂在 TBI 后几周内对突触可塑性、海马神经元存活和神经行为功能的影响。拟议的工作将对 TBI 后突触小泡分布的变化和 SNARE 复合体的变化进行首次评估。这项工作的成功完成将为我们理解突触功能障碍以及开发基于锂的方法来促进受伤大脑的恢复提供宝贵的见解。