REGULATION OF SYNAPTIC DEVELOPMENT AND FUNCTION BY NEUROTROPHIC FACTORS

该项目的主要目标是确定在视网膜、小脑和新皮层的正常发育和突触形成和功能中需要trkb介导的信号传导的细胞类型。我们将继续研究在缺乏trkB信号的情况下，从光感受器到视网膜内部的突触通讯缺陷，试图确定视网膜中哪些细胞必须表达trkB才能正常发育和光感受器的功能。我们还将描述导致观察到的突触缺陷的分子变化。在小脑内，我们将描述由

The major objectives of this project are to identify the cell types that require TrkB-mediated signaling for normal development and synapse formation and function in the retina, cerebellum and neocortex. We will continue studies that have documented deficits in synaptic communication from photoreceptors to the inner retina in the absence of trkB signaling, attempting to determine which cells in the retina must express trkB for normal development and function of photoreceptors. We will also characterize the molecular changes that result in the observed synaptic deficit. Within the cerebellum, we will characterize the phenotypes caused by absence of TrkB signaling on development of Purkinje cell spines and expression of GABAergic proteins and development of synapses by Golgi interneurons. Again, we will identify the cells where absence of trkB results in these phenotypes and will attempt to identify proteins and mRNAs altered by absence of TrkB signaling that are candidates to explain these phenotypes. We will characterize further the progressive deficit observed in the cortex of mice in which TrkB has been eliminated from the majority of cortical pyramidal cells. We will determine whether it becomes more and more progressive as animals age, determine whether there are additional secondary effects on neurons not targeted directly, and will try to identify proteins and mRNAs known to be involved in dendrite formation that depend upon TrkB signaling for normal expression. Receptor tyrosine kinase signaling obviously mediates many diverse actions in the central nervous system. It is hoped that studies on this one important tyrosine kinase will result in conclusions applicable to understanding the roles of other tyrosine kinases in addition to the Trk receptors in regulating neuronal development, function, and aging in the central nervous system in both health and disease.