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Mct8 – Effect of thyroid hormone on the brains of mice and men

Thyroid hormones are essential for embryonic development as well as for energy metabolism. Sufficient supply with maternal thyroid hormones especially during embryonic development and shortly after birth is indispensable for proper brain development and maturation. Even a transient shortage of thyroid hormone can have severe consequences as impaired hearing, intelligence or motor coordination. Thyroid hormone molecules have to pass the cell membrane in order to reach their nuclear receptors. Specialized transporter proteins, such as MCT8, mediate uptake of thyroid hormone into the cell. Recently, it has been shown that MCT8 is not functional in patients with Allan-Herndon-Dudley syndrome, a severe X-linked mental retardation syndrome.

Wirth and colleagues analysed mice in which the Mct8 gene was deliberately inactivated. These mice replicate several aspects of the human disorder, but not the mental retardation. The scientists could show for the first time that MCT8 is directly involved in the uptake of thyroid hormone into cultured neurons. In contrast to the situation in humans, additional transport proteins exist in mice which can partly compensate for the deficiency of MCT8. Accordingly, scientists from the German Mouse Clinic found slight differences in behaviour and nociception in Mct8 mutant mice. These mice were more curious and bolder than wild-type controls. In the hot plate test the mouse is placed on a hot plate and the time until it reacts is measured. Mutants showed increased sensitivity to heat (hyperalgesia). These findings support previous results that reduced anxiety and lower tolerance to pain are often associated with increased levels of thyroid hormone.

The analysis of the Mct8-deficient mice shows that the same genetic defect in mice and humans does not necessarily have the same consequences in both species. However, it is possible to learn a lot from the comparison of both organisms. To find the compensating second transporter in mouse neurons is the objective of ongoing studies.

 

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“, Wirth et al., 2009, J. Neurosci. 29(30) 137, 9439-9449