Modulation of Synaptic transmission by thyroid hormones.

Dr. Legier V. Rojas

 

The Problem: In embryonic tissue, thyroid hormones (mainly 3,5,3’ triiodothyronine, or T3) act primarily at the genomic level to regulate gene expression during transcription. The absence of THs causes permanent damage in embryonic tissues. In contrast, the actions of THs in adult tissues are primarily non-genomic, in that they are transient and reversible in the mature nervous system. Recent experiments have suggested that the acute effects of THs occur in synapses formed by embryonic neuromuscular junctions (NMJs) (Rojas, et al., 2003). Collectively these results are consistent with the hypothesis that THs have non-genomic actions in the early stages of development as well as in adulthood. Clearly, further work is needed to delineate the precise mechanisms by which THs mediate their physiological effects.

Goals: We propose to further characterize the non-genomic actions of THs in the embryonic frog NMJ. The amphibian NMJ is a well-characterized system that undergoes profound changes during development in response to T3. The primary goal of the proposed project is to further elucidate the mechanism by which THs elicit their non-genomic effects during development of both the pre- and post-synaptic regions of the amphibian NMJ.

Strategy: We will characterize the mechanisms by which THs mediate their acute actions in the pre-synaptic and post-synaptic regions of the embryonic frog NMJ. At the presynaptic level, we will continue studying the non-genomic effects of THs in both the nerve terminal and the motoneuron soma. At the post-synaptic level, we will evaluate the acute effects of THs on the postsynaptic muscle-type acetylcholine receptor (AChR)

Techniques: In addition to the conventional electrophysiological techniques that we routinely use in our laboratory, we propose to measure intracellular calcium using Ca-ratio and laser scanning confocal (LSC) microscopy and behavioral studies to evaluate the effects of THs in pre- and pro-metamorphic Rana castebeiana.

Significance: Kaczmarek and Levitan (1987) defined neuromodulation as the ability of neurons to alter their electrical properties in response to intracellular biochemical changes caused by synaptic or hormonal stimulation. In this context, neuromodulation represents a critical intrinsic feature of individual neurons. Several findings have suggested that THs play an important role in modulating neurotransmission in the central nervous system (CNS). These findings, together with the preliminary report showing that THs modulate neurotransmitter release, raise the possibility THs may act as neuromodulators within the nervous system. In view of reports that THs are colocalized with norepinephrine in noradrenergic neurons of the adult CNS, it seems plausible that these hormones may play important roles in brain function, cognition and pathological situations. Moreover, the proposed research will increase our understanding of the mechanisms by which endogenous THs modulate neuronal apoptosis and normal development. Neuronal apoptosis is now thought to play a significant role in the pathology of a number of degenerative diseases of the CNS, including Parkinson's and Alzheimer's disease, as well as in peripheral neurological disorders, such as various neuropathies and retinal degeneration. The fact that apoptosis plays a key role in these diverse physiological and pathological processes suggests that the pharmacological actions of THs represent important targets for biotechnology and for future clinical applications.

 

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