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SAT-454 A Novel Role of Thyroid Hormone Receptor in Synaptic Plasticity in Cerebellar Purkinje Cells

Thyroid hormone (TH) is essential for the development and the maintenance of the brain function. TH action is mediated by TH receptor (TR). TR binds to a specific DNA sequence on TH-target genes and thus functions as a ligand-dependent transcription factor. In thyroid diseases such as congenital hyp...

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Autores principales: Ninomiya, Ayane, Hosoi, Nobutake, Kokubo, Michifumi, Amano, Izuki, Haijima, Asahi, Miyazaki, Wataru, Hirai, Hirokazu, Koibuchi, Noriyuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7207436/
http://dx.doi.org/10.1210/jendso/bvaa046.1706
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author Ninomiya, Ayane
Hosoi, Nobutake
Kokubo, Michifumi
Amano, Izuki
Haijima, Asahi
Miyazaki, Wataru
Hirai, Hirokazu
Koibuchi, Noriyuki
author_facet Ninomiya, Ayane
Hosoi, Nobutake
Kokubo, Michifumi
Amano, Izuki
Haijima, Asahi
Miyazaki, Wataru
Hirai, Hirokazu
Koibuchi, Noriyuki
author_sort Ninomiya, Ayane
collection PubMed
description Thyroid hormone (TH) is essential for the development and the maintenance of the brain function. TH action is mediated by TH receptor (TR). TR binds to a specific DNA sequence on TH-target genes and thus functions as a ligand-dependent transcription factor. In thyroid diseases such as congenital hypothyroidism or resistance to TH (RTH), TH-TR binding is dominantly disrupted, leading to the various symptoms such as motor deficits. However, in such cases, all the cells that express TR get affected by the disrupted TR signaling; thus, the specific mechanism has not been cleared. It has been well known that proper motor coordination is deeply related to long term depression (LTD) of synaptic transmission from parallel fiber (PF) to Purkinje cell (PC) in the cerebellum (Ito, 1989). Therefore, we examined the involvement of TR in synaptic plasticity at PF-PC synapses by using transgenic mice (Mf-1 mice) which express dominant-negative TR specifically in PCs. Since Mf-1 display the impairment of motor coordination and motor learning, a decrease in TR signaling in PCs may alter synaptic plasticity and contribute to motor incoordination. A whole-cell patch clamp recording of Mf-1 PCs revealed the inhibition of LTD but instead the induction of long term potentiation (LTP) of the synaptic transmission at PF-PC synapses. This indicates that the intracellular calcium dynamics may be disrupted in Mf-1 PCs since LTD requires a higher elevation of the intracellular calcium concentration in PCs than LTP does. Indeed, single-PC qPCR showed that the mRNA levels of some important molecules for the intracellular calcium dynamics in PCs (SERCA2, IP(3)R, and P/Q-type calcium channel) are downregulated in Mf-1 PCs. This result suggests those genes as possible TH-target genes. Taken together, the present study suggested a novel possible role of TR in synaptic plasticity at PF-PC synapses by regulating the expression of some important genes for LTD occurrence in the cerebellum. This finding could give a new insight into the mechanism of motor deficits in thyroid diseases.
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spelling pubmed-72074362020-05-13 SAT-454 A Novel Role of Thyroid Hormone Receptor in Synaptic Plasticity in Cerebellar Purkinje Cells Ninomiya, Ayane Hosoi, Nobutake Kokubo, Michifumi Amano, Izuki Haijima, Asahi Miyazaki, Wataru Hirai, Hirokazu Koibuchi, Noriyuki J Endocr Soc Thyroid Thyroid hormone (TH) is essential for the development and the maintenance of the brain function. TH action is mediated by TH receptor (TR). TR binds to a specific DNA sequence on TH-target genes and thus functions as a ligand-dependent transcription factor. In thyroid diseases such as congenital hypothyroidism or resistance to TH (RTH), TH-TR binding is dominantly disrupted, leading to the various symptoms such as motor deficits. However, in such cases, all the cells that express TR get affected by the disrupted TR signaling; thus, the specific mechanism has not been cleared. It has been well known that proper motor coordination is deeply related to long term depression (LTD) of synaptic transmission from parallel fiber (PF) to Purkinje cell (PC) in the cerebellum (Ito, 1989). Therefore, we examined the involvement of TR in synaptic plasticity at PF-PC synapses by using transgenic mice (Mf-1 mice) which express dominant-negative TR specifically in PCs. Since Mf-1 display the impairment of motor coordination and motor learning, a decrease in TR signaling in PCs may alter synaptic plasticity and contribute to motor incoordination. A whole-cell patch clamp recording of Mf-1 PCs revealed the inhibition of LTD but instead the induction of long term potentiation (LTP) of the synaptic transmission at PF-PC synapses. This indicates that the intracellular calcium dynamics may be disrupted in Mf-1 PCs since LTD requires a higher elevation of the intracellular calcium concentration in PCs than LTP does. Indeed, single-PC qPCR showed that the mRNA levels of some important molecules for the intracellular calcium dynamics in PCs (SERCA2, IP(3)R, and P/Q-type calcium channel) are downregulated in Mf-1 PCs. This result suggests those genes as possible TH-target genes. Taken together, the present study suggested a novel possible role of TR in synaptic plasticity at PF-PC synapses by regulating the expression of some important genes for LTD occurrence in the cerebellum. This finding could give a new insight into the mechanism of motor deficits in thyroid diseases. Oxford University Press 2020-05-08 /pmc/articles/PMC7207436/ http://dx.doi.org/10.1210/jendso/bvaa046.1706 Text en © Endocrine Society 2020. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Thyroid
Ninomiya, Ayane
Hosoi, Nobutake
Kokubo, Michifumi
Amano, Izuki
Haijima, Asahi
Miyazaki, Wataru
Hirai, Hirokazu
Koibuchi, Noriyuki
SAT-454 A Novel Role of Thyroid Hormone Receptor in Synaptic Plasticity in Cerebellar Purkinje Cells
title SAT-454 A Novel Role of Thyroid Hormone Receptor in Synaptic Plasticity in Cerebellar Purkinje Cells
title_full SAT-454 A Novel Role of Thyroid Hormone Receptor in Synaptic Plasticity in Cerebellar Purkinje Cells
title_fullStr SAT-454 A Novel Role of Thyroid Hormone Receptor in Synaptic Plasticity in Cerebellar Purkinje Cells
title_full_unstemmed SAT-454 A Novel Role of Thyroid Hormone Receptor in Synaptic Plasticity in Cerebellar Purkinje Cells
title_short SAT-454 A Novel Role of Thyroid Hormone Receptor in Synaptic Plasticity in Cerebellar Purkinje Cells
title_sort sat-454 a novel role of thyroid hormone receptor in synaptic plasticity in cerebellar purkinje cells
topic Thyroid
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7207436/
http://dx.doi.org/10.1210/jendso/bvaa046.1706
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