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Importance of Monocarboxylate Transporter 8 for the Blood-Brain Barrier-Dependent Availability of 3,5,3'-Triiodo-L-Thyronine

Instituto de Investigaciones Biomedicas (A.C., M.M.B., E.S.-M., J.B.), Consejo Superior de Investigaciones Cientificas and Universidad Autonoma de Madrid, 28029 Madrid, Spain; Center for Biomedical Research on Rare Diseases (C.G.-M., B.M., J.B.), 28029 Madrid, Spain; and Departments of Medicine (A.M.D., S.R.) and Pediatrics (S.R.), University of Chicago, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Beatriz Morte or Juan Bernal, Instituto de Investigaciones Biomédicas, Arturo Duperier 4, 28029 Madrid, Spain. E-mail: bmorte{at}iib.uam.es or jbernal{at}iib.uam.es.

Mutations of the gene expressing plasma membrane transporter for thyroid hormones MCT8 (SLC16A2) in humans lead to altered thyroid hormone levels and a severe neurodevelopmental disorder. Genetically engineered defect of the Mct8 gene in mice leads to similar thyroid hormone abnormalities but no obvious impairment of brain development or function. In this work we studied the relative role of the blood-brain barrier and the neuronal plasma cell membrane in the restricted access of T₃ to the target neurons. To this end we compared the effects of low doses of T₄ and T₃ on cerebellar structure and gene expression in wild-type (Wt) and Mct8 null male mice [Mct8-/y, knockout (KO)] made hypothyroid during the neonatal period. We found that compared with Wt animals, T₄ was considerably more potent than T₃ in the Mct8KO mice, indicating a restricted access of T₃, but not T₄, to neurons after systemic administration in vivo. In contrast, T₃ action in cultured cerebellar neurons was similar in Wt cells as in Mct8KO cells. The results suggest that the main restriction for T₃ entry into the neural target cells of the mouse deficient in Mct8 is at the blood-brain barrier.

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