REGULATION OF SYNAPTIC DEVELOPMENT AND FUNCTION BY NEUROTROPHIC FACTORS

该项目的主要目标是确定在视网膜、小脑和新皮质中需要TrkB介导的信号来实现正常发育和突触形成和功能的细胞类型。我们将继续研究在没有TrkB信号的情况下从光感受器到视网膜内部的突触通信缺陷，试图确定视网膜中的哪些细胞必须表达TrkB才能正常发育和发挥光感受器的功能。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 缺乏TrkB信号对浦肯野细胞棘的发育、高尔基体中间神经元GABA能蛋白的表达和突触的发育。同样，我们将鉴定TrkB缺失导致这些表型的细胞，并试图鉴定因缺少TrkB信号而改变的蛋白质和mRNAs，这些蛋白质和mRNAs是解释这些表型的候选基因。我们将进一步描述在小鼠皮质中观察到的进行性缺陷，在这些小鼠中，TrkB已经从大多数皮质锥体细胞中消除。我们将确定它是否随着动物年龄的增长而变得越来越进步，确定是否对没有直接靶向的神经元产生额外的次要影响，并将尝试识别蛋白质和 已知的参与树突形成的mRNAs依赖于TrkB信号的正常表达。受体酪氨酸激酶信号明显地在中枢神经系统中介导许多不同的活动。人们希望，对这一重要酪氨酸激酶的研究将得出适用于理解除Trk受体之外的其他酪氨酸激酶在调节中枢神经系统中的神经发育、功能和衰老方面的作用的结论。

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.