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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

基本信息

批准号：
8977261
负责人：
SHAUN CARLSON
金额：
$ 5.42万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/8977261
关键词：
Acetylcholine Acute Aminobutyric Acids Attenuated Behavioral Biological Assay Brain 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 improved injured insight motor disorder mouse model neurobehavioral neurotransmission neurotransmitter release novel presynaptic public health relevance receptor reconstruction synaptic function syntaxin

项目摘要

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.