Ainhoa Ceballos*, Monica M. Belinchon*, Eduardo Sanchez-Mendoza, Carmen Grijota- Martinez, Alexandra M. Dumitrescu, Samuel Refetoff, Beatriz Morte, and Juan Bernal

Abstract: 

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, KO) made hypothyroid during the neonatal period. We found that compared to 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.