Synaptic Remodeling and Thyroid Hormones

这个项目的主要目标是阐明甲状腺激素通过何种分子机制 调节脊椎动物神经肌肉接头的神经肌肉传递。拟议的研究将 解决一系列关于甲状腺激素(TH)在 哺乳动物神经肌肉接头(NMJ)。THs对哺乳动物突触前后的影响 将对端板进行角色化。提出了以下三个目标： 目的1.工作假设是TH控制基础微终板电流(MEPC)频率。 在分目标1a中，我们建议描述THs对自发神经递质的急性作用。 从哺乳动物NMJ的突触前元件释放。子目标1b，已被设计为 描述THs非转录作用的分子机制。 目的2.我们认为TH水平的改变会引起自发动物的变化 运动，这可以用外周的动作来解释。我们将研究这些水平的变化是如何 产生表型改变(如自发活动、饲养等)在短期和长期 甲减和甲亢小鼠。此外，我们将把这些表型修饰与结构相关。 用共聚焦显微镜评估NMJ元素的变化。 目的3.我们假设TH可以直接与突触后乙酰胆碱受体(AChR)相互作用 频道。我们计划直接评估这种相互作用，评估肌肉中AChR通道的活性 用外向贴片和快速灌流从对照组、甲状腺功能低下和甲状腺功能亢进小鼠分离纤维 方法论。 这些研究将我们先前的工作扩展到第二阶段，在该阶段中开发了各种方法 在过去的两年中将被应用于定义哺乳动物中THs的影响的生理方面 NMJ。数以百万计的美国人(接近总人口的2%)受到甲状腺功能障碍的影响。有一个 我们目前对神经中这种作用的基本机制的理解存在差异 系统和已知提供的有益效果。

The primary goal of this project is to elucidate the molecular mechanisms by which thyroid hormones regulate the neuromuscular transmission at the vertebrate neuromuscular junction. The proposed studies will address a series of fundamental questions regarding the action of Thyroid hormones (THs) in the mammalian neuromuscular junction (NMJ). The pre- and post-synaptic effects of THs on the mammalian endplate will be characterized. The following 3 aims are proposed: Aim 1. The working hypothesis is that THs control the basal miniature endplate current (MEPC) frequency. In sub-aim 1a, we propose to characterize the acute action of THs on the spontaneous neurotransmitter release from the presynaptic element of the mammalian NMJ. Sub-aim1b, have been designed to characterize the molecular mechanism involved in the non-transcriptional action of THs. Aim 2. We propose that the modification of THs levels cause changes in the spontaneous animal locomotion, which can be explained by peripheral THs' action. We will study how alterations in THs levels produce phenotype modifications (i.e., in spontaneous locomotion, rearing, etc.) in short-term and long-term hypo- and hyperthyroid mice. Furthermore, we will correlate these phenotype modifications with structural variation in the NMJ elements evaluated using confocal microscopy. Aim 3. We hypothesize that THs could interact directly with the postsvnaptic acetvlcholine receptor (AChR) channel. We plan to directly assess this interaction evaluating the activity of the AChR channel in muscle fibers dissociate from Control, hypo- and hyper-thyroid mice using outside-out patches and fast perfusion methodology. These studies extend our previous work to a second phase, in which a variety of approaches developed during the last two years will be applied to define physiological aspects of the effects of THs in mammalian NMJ. Millions of Americans (near 2% of the population) are affected by thyroid dysfunction. There is a disparity between our current understandings of the basic mechanism underlying THs action in the nervous system and the beneficial effects that THs are known to provide.