ALTERED EXCITATORY NEUROTRANSMISSION AFTER BRAIN TRAUMA

脑外伤后兴奋性神经传递发生改变

• 批准号: 7921799
• 负责人: LESLIE S. SATIN
• 金额: $ 4万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-03 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7921799
• 关键词: Acids; Address; Attenuated; Biochemical; Brain region; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Cells; Cessation of life; Cognition Disorders; Cognitive; Cognitive deficits; Communication; Confocal Microscopy; Development; Electrophysiology (science); Event; Exhibits; Frequencies; Functional disorder; Future; Glutamate Receptor; Hippocampus (Brain); In Vitro; Individual; Injury; Intervention; Kinetics; Long-Term Potentiation; Mechanics; Mediating; Modeling; Molecular; Morphology; Motor; N-Methylaspartate; Neurons; Nootropic Agents; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phosphorylation; Phosphotransferases; Property; Protein Analysis; Regulation; Research; Research Personnel; Signal Transduction; Stimulus; Stretching; Synapses; Synaptic Receptors; Synaptic Transmission; Synaptic plasticity; System; Testing; Time; Trauma; Traumatic Brain Injury; Western Blotting; aspartate receptor; design; hippocampal pyramidal neuron; immunocytochemistry; improved; in vivo; information processing; injured; insight; motor deficit; neurotransmission; novel; patch clamp; phosphatase inhibitor; postsynaptic; presynaptic; prevent; programs; receptor; response; synaptic function; transmission process

Traumatic brain injury (TBI)results in cognitive and motor deficits involving altered excitatory neurotransmission and plasticity, including a loss of long term potentiation (LTP). Abnormal excitatory synaptic function could result from changes in network circuitry, synapse number or morphology, and/or presynaptic or postsynaptic neuronal function. The overall objective of our research is to understand the mechanisms involved in TBI-induced alterations of excitatory transmission at the electrophysiological, biochemical and molecular level. Our hypothesis is that TBI-induced changes in the properties and/or regulation of postsynaptic glutamate receptors contribute to the alterations in synaptic function and information processing observed in surviving neurons after TBI. In vitro traumatic injury produces highly novel changes in neuronal glutamate receptors, which mediate excitatory synaptic transmission and plasticity. Patch clamp electrophysiology, confocal microscopy, immunocytochemistry, and Western blot analysis will be used to study cultured cortical and hippocampal pyramidal neurons sub lethally injured using the in vitro stretch model. We will determine whether injury-induced changes in excitatory postsynaptic currents are due to direct alterations in postsynaptic AMPA and NMDA receptors and identify the specific intracellular signaling systems involved, which we hypothesize may include calcium/calmodulin kinase II, and PKC. Furthermore, we will determine whether activation of these intracellular pathways following injury leads to abnormal glutamate receptor phosphorylation during basal synaptic transmission and under conditions that normally induce synaptic plasticity. Carrying out these Specific Aims will elucidate how mechanical injury alters excitatory synaptic transmission and synaptic regulation in both the cortex and hippocampus and determine if these alterations are mediated by changes in postsynaptic glutamate receptors, including abnormal receptor phosphorylation. An understanding of the molecular mechanisms responsible for abnormal synaptic transmission in specific brain regions following TBI may assist in the development of new TBI treatments and will help direct future research of cognitive and motor deficits following in vivo TBI.

创伤性脑损伤（TBI）导致涉及改变兴奋性的认知和运动缺陷 神经传递和可塑性，包括长期增强（LTP）的损失。异常兴奋性 突触功能可能是由于网络电路，突触数或形态的变化以及/或 突触前或突触后神经元功能。我们研究的总体目的是了解 与TBI诱导的电生理学兴奋性传播改变有关的机制， 生化和分子水平。我们的假设是TBI诱导的性质变化和/或 突触后谷氨酸受体的调节有助于突触功能的改变和 TBI后在幸存的神经元中观察到的信息处理。体外创伤性损伤高度产生 神经元谷氨酸受体的新变化，介导兴奋性突触传播和 可塑性。斑块夹电生理学，共聚焦显微镜，免疫细胞化学和蛋白质印迹 分析将用于研究培养的皮质和海马锥体神经元，使用 体外拉伸模型。我们将确定受伤引起的兴奋性突触的变化是否变化 电流是由于突触后AMPA和NMDA受体的直接改变所致，并确定了特定 涉及的细胞内信号传导系统，我们假设的可能包括钙/钙调蛋白激酶II和 PKC。此外，我们将确定损伤导线后这些细胞内途径的激活是否激活 在基础突触传播期间和条件下，以异常的谷氨酸受体磷酸化 通常会引起突触可塑性。执行这些特定目标将阐明机械损伤 改变皮质和海马的兴奋性突触传播和突触调节 确定这些改变是否是通过突触后谷氨酸受体的变化来介导的，包括 异常受体磷酸化。对负责分子机制的理解 TBI之后特定大脑区域的突触传播异常可能有助于开发新的 TBI治疗方法将有助于指导未来对体内TBI认知和运动缺陷的研究。