Stabilizing the tripartite synaptic complex following TBI

摘要：创伤性脑损伤是一种毁灭性的世界性疾病，被认为是 到2020年，导致患者死亡的第三大最普遍的健康问题。对人脑的创伤是一种 由多种因素引起的极其困难的问题，包括：大脑复杂性、脑损伤多样性、 大量的细胞靶点，以及损伤的进行性。我们在动物身上模拟脑损伤的能力至关重要 用于制定治疗策略，将损害降至最低和/或促进恢复。的一个共同特征 从脑震荡到穿透性损伤，脑外伤是一种弥漫性和进行性突触损伤，最终 会导致功能丧失。我们的研究将模拟在没有神经元丢失的情况下的突触损伤。 海马体研究进行性突触损伤的作用机制。我们假设 海马谷氨酸能神经元共递质D-丝氨酸的时相释放 在调节突触功能中起重要作用；然而，损伤后神经元中D-丝氨酸被抑制，但 在星形胶质细胞中上调。星形细胞D-丝氨酸的紧张性释放增加导致亚致死性兴奋毒性突触 受伤后第一周内的损害。我们还发现，增强的星形细胞D-丝氨酸水平是 受三叉神经突触内神经元-星形胶质细胞通讯的调节。具体地说，我们假设 神经元性EphinB3与星形细胞EphB3和EphA4通讯，调节D-丝氨酸的产生和 放手。脑外伤后，反应性星形胶质细胞中Eph信号水平的升高导致过量释放 D-丝氨酸。我们的研究采取了一种综合的方法来解决我们的假设使用尖端 研究D-丝氨酸调节机制的技术和细胞特异性基因敲除和敲除小鼠 介导的突触功能和功能障碍。

Summary: Traumatic brain injury (TBI) is a devastating worldwide disorder, and is believed to become the third most prevalent health concern contributing to patient mortality by 2020. Trauma to the human brain is an extremely difficult problem that arises from numerous factors including; brain complexity, TBI diversity, numerous cellular targets, and the progressive nature of the injury. Our ability to model TBI in animals is critical for developing therapeutic strategies to minimize damage and/or promote recovery. One common feature of TBI, ranging from concussive to penetrating injuries, is diffuse and progressive synaptic damage that ultimately leads to functional losses. Our studies will model synaptic damage in the absence of neuron losses in the hippocampus to examine mechanisms of action that underlie progressive synaptic damage. We hypothesize that the phasic release of the co-transmitter D-serine from hippocampal glutaminergic neurons plays an important role in regulating synaptic function; however, following injury D-serine is suppressed in neurons but up regulated in astrocytes. Increased tonic release of astrocytic D-serine leads to sub-lethal excititoxic synaptic damage over the first week post-injury. We have also found that enhanced astrocytic D-serine levels are regulated by neuronal-astrocyte communication in the tripartite synapse. Specifically, we hypothesize that neuronal ephrinB3 communicates with astrocytic EphB3 and EphA4 to regulate D-serine production and release. Following TBI, increased levels of Eph signaling in reactive astrocytes results in excessive release of D-serine. Our studies take a comprehensive approach to address our hypotheses using cutting edge techniques and cell specific knockout and knockin mice to investigate the mechanisms that regulate D-serine mediated synaptic function and dysfunction.