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The Journal of Neuroscience, July 29, 2009, 29(30):9439-9449; doi:10.1523/JNEUROSCI.6055-08.2009

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Neurobiology of Disease
Neuronal 3',3,5-Triiodothyronine (T₃) Uptake and Behavioral Phenotype of Mice Deficient in Mct8, the Neuronal T₃ Transporter Mutated in Allan–Herndon–Dudley Syndrome

Eva K. Wirth,^1,4 * Stephan Roth,^1,4 * Cristiane Blechschmidt,² Sabine M. Hölter,⁶ Lore Becker,^7,8 Ildiko Racz,^7,9 Andreas Zimmer,⁹ Thomas Klopstock,⁸ Valerie Gailus-Durner,⁷ Helmut Fuchs,⁷ Wolfgang Wurst,⁶ Thomas Naumann,³ Anja Bräuer,³ Martin Hrabé de Angelis,⁷ Josef Köhrle,⁵ Annette Grüters,⁴ and Ulrich Schweizer^1,5

¹Neuroscience Research Center, ²Institute for Neuropathology, and ³Institute for Cell Biology and Neurobiology, Charité Universitätsmedizin Berlin, D-10117 Berlin, Germany, ⁴Institute for Experimental Pediatric Endocrinology and ⁵Institute for Experimental Endocrinology, Charité Universitätsmedizin Berlin, D-13353 Berlin, Germany, ⁶Institute of Developmental Genetics and ⁷Institute of Experimental Genetics, Helmholtz Zentrum München, D-85764 Munich, Germany, ⁸Friedrich Baur Institute, Department of Neurology, Ludwig-Maximilians-Universität München, D-80336 Munich, Germany, and ⁹Institute of Molecular Psychiatry, University of Bonn, D-53127 Bonn, Germany

Correspondence should be addressed to either Annette Grüters or Ulrich Schweizer, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany. E-mail: Email: annette.grueters{at}charite.de or Email: ulrich.schweizer{at}charite.de

Thyroid hormone transport into cells requires plasma membrane transport proteins. Mutations in one of these, monocarboxylate transporter 8 (MCT8), have been identified as underlying cause for the Allan–Herndon–Dudley syndrome, an X-linked mental retardation in which the patients also present with abnormally high 3',3,5-triiodothyronine (T₃) plasma levels. Mice deficient in Mct8 replicate the thyroid hormone abnormalities observed in the human condition. However, no neurological deficits have been described in mice lacking Mct8. Therefore, we subjected Mct8-deficient mice to a comprehensive immunohistochemical, neurological, and behavioral screen. Several behavioral abnormalities were found in the mutants. Interestingly, some of these behavioral changes are compatible with hypothyroidism, whereas others rather indicate hyperthyroidism. We thus hypothesized that neurons exclusively dependent on Mct8 are in a hypothyroid state, whereas neurons expressing other T₃ transporters become hyperthyroid, if they are exposed directly to the high plasma T₃. The majority of T₃ uptake in primary cortical neurons is mediated by Mct8, but pharmacological inhibition suggested functional expression of additional T₃ transporter classes. mRNAs encoding six T₃ transporters, including L-type amino acid transporters (LATs), were coexpressed with Mct8 in isolated neurons. We then demonstrated Lat2 expression in cultured neurons and throughout murine brain development. In contrast, LAT2 is expressed in microglia in the developing human brain during gestation, but not in neurons. We suggest that lack of functional complementation by alternative thyroid hormone transporters in developing human neurons precipitates the devastating neurodevelopmental phenotype in MCT8-deficient patients, whereas Mct8-deficient mouse neurons are functionally complemented by other transporters, for possibly Lat2.

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Received Dec. 19, 2008; revised April 24, 2009; accepted May 25, 2009.

Correspondence should be addressed to either Annette Grüters or Ulrich Schweizer, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany. E-mail: Email: annette.grueters{at}charite.de or Email: ulrich.schweizer{at}charite.de

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				A. Kinne, S. Roth, H. Biebermann, J. Kohrle, A. Gruters, and U. Schweizer Surface translocation and tri-iodothyronine uptake of mutant MCT8 proteins are cell type-dependent J. Mol. Endocrinol., December 1, 2009; 43(6): 263 - 271. [Abstract] [Full Text] [PDF]

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