ALTERED EXCITATORY NEUROTRANSMISSION AFTER BRAIN TRAUMA

脑外伤后兴奋性神经传递发生改变

• 批准号: 7201888
• 负责人: LESLIE S. SATIN
• 金额: $ 31.99万
• 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 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7201888
• 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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：创伤性脑损伤（TBI）导致认知和运动缺陷，涉及兴奋性神经传递和可塑性的改变，包括长期增强（LTP）的丧失。异常的兴奋性突触功能可能是由网络回路、突触数量或形态、突触前或突触后神经元功能的改变引起的。我们研究的总体目标是在电生理、生化和分子水平上了解脑外伤引起的兴奋传递改变的机制。我们的假设是，脑外伤引起的突触后谷氨酸受体性质和/或调节的变化有助于脑外伤后存活神经元突触功能和信息处理的改变。在体外创伤性损伤中，介导兴奋性突触传递和可塑性的神经元谷氨酸受体发生了高度新颖的变化。采用膜片钳电生理、共聚焦显微镜、免疫细胞化学和Western blot分析方法研究体外拉伸模型培养的皮层和海马锥体神经元亚致死损伤。我们将确定损伤引起的兴奋性突触后电流的变化是否由于突触后AMPA和NMDA受体的直接改变，并确定涉及的特定细胞内信号系统，我们假设可能包括钙/钙调蛋白激酶II和PKC。此外，我们将确定损伤后这些细胞内通路的激活是否会在基础突触传递和正常诱导突触可塑性的条件下导致谷氨酸受体磷酸化异常。开展这些特异性目的将阐明机械损伤如何改变皮层和海马中的兴奋性突触传递和突触调节，并确定这些改变是否由突触后谷氨酸受体的变化介导，包括受体异常磷酸化。了解脑外伤后特定脑区突触传递异常的分子机制可能有助于开发新的脑外伤治疗方法，并有助于指导未来脑外伤后认知和运动缺陷的研究。