Synaptic Remodeling and Thyroid Hormones

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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.