Modulating Post-Injury Gliotransmitter Levels Leads to Improved Synaptic Function

描述（由申请人提供）：创伤性脑损伤（TBI）导致许多急性病理改变，包括谷氨酸3-5的细胞外释放。这种急性递质释放被认为在早期神经元细胞死亡中起重要作用6,7。尽管进行性突触损伤在功能丧失中也起着重要作用，但不幸的是，我们对脑损伤后数天和数周内递质调节的了解有限。胶质细胞，特别是星形胶质细胞，通过调节突触间隙中的递质水平，在维持突触损伤后的完整性和功能方面发挥重要作用9-12。此外，一个受体酪氨酸激酶家族，即Eph受体及其同源配体ephrin调节星形胶质细胞的突触功能和形成以及递质合成和释放13-17。我们假设神经元通过ephrinB3-EphB3信号与星形胶质细胞沟通，调节突触中的胶质递质水平，通过增强EphB3信号可以改善脑损伤后突触的稳定性和功能。在这项研究中，我们将研究如何通过基因操作改变星形胶质细胞和/或神经元中的递质酶（即丝氨酸消旋酶）和ephrinB3-EphB3信号传导的递质水平影响脑外伤后突触的稳定性和功能。我们将采用综合的方法，利用尖端的技术来测量突触传递，递质释放，蛋白质表达的生化改变，以及使用功能获得和功能丧失的小鼠模型的学习和记忆行为。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) results in a number of acute pathological alterations including the extracellular release of glutamate3-5. This acute transmitter release is thought to play a significant role in early neuronal cell death6,7. Although progressive synaptic damage also plays a significant role in functional loss8, and unfortunately our understanding of transmitter regulation in the days and weeks after TBI is limited. Glial cells in particular astrocytes, play an important role in maintaining synaptic integrity and function aftr injury by regulating transmitter levels in the synaptic cleft9-12. In addition, a family of recepto tyrosine kinases, Eph receptors, and their cognate ligands, ephrins, regulates synaptic function and formation as well as transmitter synthesis and release from astrocytes13-17. We hypothesize that neurons communicate with astrocytes through ephrinB3-EphB3 signaling to regulate glial transmitter levels in the synapse, and through enhancement of EphB3 signaling we can improve synaptic stability and function after TBI. In this study, we will examine how varying transmitter levels through genetic manipulation of transmitter enzymes (i.e. serine racemase) and ephrinB3-EphB3 signaling in astrocytes and/or neurons affects synaptic stability and function after TBI. We will take a comprehensive approach and make use of cutting-edge techniques to measure synaptic transmission, transmitter release, biochemical alterations in protein expression, and learning and memory behavior using gain-of-function and loss-of-function mouse models.