ALTERED EXCITATORY NEUROTRANSMISSION AFTER BRAIN TRAUMA

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，包括长时程增强（LTP）的丧失。异常兴奋性 突触功能可以由网络电路、突触数量或形态的变化引起，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 TBI诱导的兴奋性传递在电生理学上的改变涉及的机制， 生物化学和分子水平。我们的假设是，TBI诱导的性质和/或 突触后谷氨酸受体的调节有助于突触功能的改变， 在TBI后存活的神经元中观察到的信息处理。体外创伤性损伤 神经元谷氨酸受体的新变化，其介导兴奋性突触传递， 可塑性膜片钳电生理学、共聚焦显微镜、免疫细胞化学和Western印迹 分析将用于研究培养的皮质和海马锥体神经元亚致死损伤， 体外拉伸模型。我们将确定是否损伤诱导的兴奋性突触后神经元的变化， 电流是由于突触后AMPA和NMDA受体的直接改变，并确定了特定的 涉及的细胞内信号系统，我们假设可能包括钙/钙调蛋白激酶II， 蛋白激酶C此外，我们将确定损伤后这些细胞内通路的激活是否导致 异常谷氨酸受体磷酸化在基础突触传递和条件下 通常会诱发突触可塑性。执行这些具体目标将阐明机械损伤如何 改变皮质和海马中的兴奋性突触传递和突触调节， 确定这些改变是否由突触后谷氨酸受体的变化介导，包括 受体磷酸化异常。了解导致癌症的分子机制 TBI后特定脑区的异常突触传递可能有助于新的 TBI治疗，并将有助于指导未来的研究认知和运动缺陷后，在体内TBI。

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.