Thyroid hormones and synaptic function

虽然甲状腺激素在神经系统发育过程中是必需的，但其作用的分子基础尚不清楚。本项目的长期目标是阐明胚胎组织中THs调节突触功能的分子机制。蝌蚪尾部的神经肌肉连接处（NMJ）是研究神经调节的一个很好的系统，因为它在THs的存在下以凋亡的方式死亡。具体目标确定胆碱能受体和神经末梢在蝌蚪尾部发育的几个阶段的分布，这一突触系统的解剖特征的表征是了解这一非基因组作用的第一步。我们将验证这一假设，即负责突触传递的achr优先位于肌肉纤维的极端吻侧。具体目标2。确定三萜类化合物对突触囊泡循环的急性突触前作用及其与细胞内钙水平的关系。我们将检验mepc频率增强的假设

Although thyroid hormones (THs) are strictly required during developing nervous system, the molecular bases of their action are poorly understood. The long-term goal of this project is to elucidate the molecular mechanism by which synaptic function is modulated by THs in embryonic tissue. The Neuromuscular junction (NMJ) of tadpole tail is an excellent system to study neuromodulation, because it dies by apoptosis in the presence of THs. Specific Aim 1. Determine the distribution of cholinergic receptors and nerve terminals tadpole tails at several stages of development, The Characterization of the anatomical features of this synaptic system represents the first step towards understanding the non-genomic actions of THs. We will test the hypothesis that the AChRs responsible for synaptic transmission are preferential/y located within the extreme rostral of the muscular fiber. Specific Aim 2. Determine the acute pre-synaptic action of THs on synaptic vesicle recycling and its relationship to intracellular calcium level. We will test the hypothesis that the enhanced mepc frequency observed in response to T3 results from augmented vesicle recycling. Two separated sub-aims will be considered: (a) to determine the role of THs in modulating vesicle recycling, and (b) to assess the role of intracellu/ar calcium level in mediating the actions of TH. Specific Aim 3. Assess the acute postsynaptic action of thyroid hormones on the AChR. We will test the hypothesis that THs interact directly with the postsynaptic AC-receptor and secondly that the calcium mobilization by the AChR that is alter by T3 causes chanties in the AChR kinetic activity. The experiments will include three powerful techniques: Near Infrared (NIR) microscopy, Laser Scanning Confocal Microscopy (LSCM) and conventional electrophysiology. High and low affinity calcium dyes will be used to evaluate calcium levels in the pre- and post-synaptic regions. This study will provide information that is relevant to clinical applications including treatments in which T3 is being co-administrated and/or used. Importantly, neuronal apoptosis is now thought to play a significant role in the pathology of a number of degenerative diseases of the CNS (e.g. Parkinson's and Alzheimer's diseases) as well as in the periphery (for example, various neuropathies and retinal degeneration). The key role of apoptosis in these diverse physiological and pathological processes suggests that the pharmacology of apoptosis and the actions of THs will become important targets for biotechnology and for clinical applications.