Importance of monocarboxylate transporter 8 for the blood-brain barrier-dependent availability of 3,5,3'-triiodo-L-thyronine.
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 T(3) to the target neurons. To this end we compared the effects of low doses of T(4) and T(3) 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, T(4) was considerably more potent than T(3) in the Mct8KO mice, indicating a restricted access of T(3), but not T(4), to neurons after systemic administration in vivo. In contrast, T(3) action in cultured cerebellar neurons was similar in Wt cells as in Mct8KO cells. The results suggest that the main restriction for T(3) entry into the neural target cells of the mouse deficient in Mct8 is at the blood-brain barrier.
Ceballos
Ainhoa
A
Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Cientificas and Universidad Autonoma de Madrid, 28029 Madrid, Spain.
Belinchon
Monica M
MM
Sanchez-Mendoza
Eduardo
E
Grijota-Martinez
Carmen
C
Dumitrescu
Alexandra M
AM
Refetoff
Samuel
S
Morte
Beatriz
B
Bernal
Juan
J
D000818:Animals; D000831:Animals, Newborn; D001692:Biological Transport / Q000235:genetics; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D027501:Monocarboxylic Acid Transporters; D051579:Neurogranin / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D027981:Symporters; D014284:Triiodothyronine / Q000378:metabolism*
D026901:Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; C496650:Nrgn protein, mouse; C484257:Slc16a2 protein, mouse; D027981:Symporters; D014284:Triiodothyronine; D051579:Neurogranin