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The Journal of Neuroscience, February 20, 2008, 28(8):1904-1915; doi:10.1523/JNEUROSCI.5163-07.2008

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Neurobiology of Disease
Locomotor Deficiencies and Aberrant Development of Subtype-Specific GABAergic Interneurons Caused by an Unliganded Thyroid Hormone Receptor 1

Karin Wallis,^1 * Maria Sjögren,^1 * Max van Hogerlinden,¹ Gilad Silberberg,² André Fisahn,² Kristina Nordström,¹ Lars Larsson,⁴ Håkan Westerblad,³ Gabriela Morreale de Escobar,⁵ Oleg Shupliakov,² and Björn Vennström¹

Departments of ¹Cell and Molecular Biology, ²Neuroscience, and ³Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden, ⁴Department of Neuroscience, Uppsala University, SE-751 24 Uppsala, Sweden, and ⁵Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid and Center for Biomedical Research on Rare Diseases, 28029 Madrid, Spain

Correspondence should be addressed to Prof. Björn Vennström, Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, Box 285, SE-171 77 Stockholm, Sweden. Email: bjorn.vennstrom{at}ki.se

Thyroid hormone (TH) deficiency during development causes severe and permanent neuronal damage, but the primary insult at the tissue level has remained unsolved. We have defined locomotor deficiencies in mice caused by a mutant thyroid hormone receptor 1 (TR1) with potent aporeceptor activity attributable to reduced affinity to TH. This allowed identification of distinct functions that required either maternal supply of TH during early embryonic development or sufficient innate levels of hormone during late fetal development. In both instances, continued exposure to high levels of TH after birth and throughout life was needed. The hormonal dependencies correlated with severely delayed appearance of parvalbumin-immunoreactive GABAergic interneurons and increased numbers of calretinin-immunoreactive cells in the neocortex. This resulted in reduced numbers of fast spiking interneurons and defects in cortical network activity. The identification of locomotor deficiencies caused by insufficient supply of TH during fetal/perinatal development and their correlation with subtype-specific interneurons suggest a previously unknown basis for the neuronal consequences of endemic cretinism and untreated congenital hypothyroidism, and specifies TR1 as the receptor isoform mediating these effects.

Key words: thyroid hormone receptor; parvalbumin; calretinin; GABA; hypothyroid; interneuron; locomotion

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Received Sept. 4, 2007; revised Jan. 6, 2007; accepted Jan. 6, 2008.

Correspondence should be addressed to Prof. Björn Vennström, Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, Box 285, SE-171 77 Stockholm, Sweden. Email: bjorn.vennstrom{at}ki.se

This article has been cited by other articles:

				M. Vujovic, K. Nordstrom, K. Gauthier, F. Flamant, T. J. Visser, B. Vennstrom, and J. Mittag Interference of a Mutant Thyroid Hormone Receptor {alpha}1 with Hepatic Glucose Metabolism Endocrinology, June 1, 2009; 150(6): 2940 - 2947. [Abstract] [Full Text] [PDF]

				R. A. Sinha, A. Pathak, V. Mohan, S. Bandyopadhyay, L. Rastogi, and M. M. Godbole Maternal Thyroid Hormone: A Strong Repressor of Neuronal Nitric Oxide Synthase in Rat Embryonic Neocortex Endocrinology, September 1, 2008; 149(9): 4396 - 4401. [Abstract] [Full Text] [PDF]

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