ALTERED EXCITATORY NEUROTRANSMISSION AFTER BRAIN TRAUMA

脑外伤后兴奋性神经传递发生改变

• 批准号: 7338310
• 负责人: LESLIE S. SATIN
• 金额: $ 20.22万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 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 2008-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7338310
• 关键词: Acids; Address; Attenuated; Biochemical; Brain region; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Cells; Cessation of life; Chromosome Pairing; Cognition Disorders; Cognitive; Cognitive deficits; Communication; Computer information processing; Condition; 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; Numbers; 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; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; aspartate receptor; design; hippocampal pyramidal neuron; immunocytochemistry; improved; in vivo; 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.

创伤性脑损伤导致认知和运动障碍，涉及兴奋性改变。 神经传递和可塑性，包括长时程增强(LTP)的丧失。异常兴奋 突触功能可由网络回路、突触数量或形态的改变和/或 突触前或突触后神经元功能。我们研究的总体目标是了解 脑损伤引起电生理兴奋性传递改变的机制， 生化和分子水平。我们的假设是，脑损伤导致的属性和/或 突触后谷氨酸受体的调节参与突触功能的改变和 脑外伤后存活神经元的信息处理观察。体外创伤性损伤产生的 神经元谷氨酸受体的新变化，它介导兴奋性突触传递和 可塑性。膜片钳电生理学、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区锥体神经元亚致死性损伤 体外拉伸模型。我们将确定损伤是否会导致兴奋性突触后的变化 电流是由突触后AMPA和NMDA受体的直接变化引起的，并识别特定的 参与的细胞内信号系统，我们推测可能包括钙/钙调蛋白激酶II，以及 PKC。此外，我们将确定损伤后这些细胞内通路的激活是否会导致 谷氨酸受体在基础突触传递过程中的异常磷酸化 正常情况下会诱发突触可塑性。实现这些特定的目标将阐明机械性损伤 改变皮层和海马区兴奋性突触传递和突触调节 确定这些变化是否由突触后谷氨酸受体的变化所介导，包括 受体磷酸化异常。对致病分子机制的理解 脑外伤后特定脑区突触传递异常可能有助于新的脑损伤的发生 并将有助于指导体内脑外伤后认知和运动障碍的未来研究。