REGULATION OF SYNAPTIC DEVELOPMENT AND FUNCTION BY NEUROTROPHIC FACTORS

该项目的主要目标是确定需要TrkB介导的信号传导的细胞类型，用于视网膜，小脑和新皮质中的正常发育和突触形成和功能。我们将继续研究已经记录的缺乏trkB信号传导的情况下从光感受器到视网膜内层的突触通信的缺陷，试图确定视网膜中的哪些细胞必须表达trkB以实现光感受器的正常发育和功能。我们还将描述导致所观察到的突触缺陷的分子变化。在小脑内，我们将描述由以下原因引起的表型： TrkB信号传导的缺乏对浦肯野细胞棘的发育和GABA能蛋白的表达以及高尔基体中间神经元的突触发育的影响。同样，我们将鉴定其中缺乏TrkB导致这些表型的细胞，并将尝试鉴定因缺乏TrkB信号传导而改变的蛋白质和mRNA，其是解释这些表型的候选物。我们将进一步表征在TrkB已从大多数皮质锥体细胞中消除的小鼠皮质中观察到的进行性缺陷。我们将确定它是否随着动物年龄的增长而变得越来越渐进，确定是否对不直接靶向的神经元有额外的次级效应，并将尝试识别蛋白质和 已知参与树突形成的mRNA依赖于TrkB信号传导以正常表达。受体酪氨酸激酶信号传导显然介导中枢神经系统中的许多不同的行动。希望对这一重要酪氨酸激酶的研究将得出适用于理解除Trk受体外的其他酪氨酸激酶在调节中枢神经系统中的神经元发育、功能和衰老的健康和疾病中的作用的结论。

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.