Thyroid Hormones in Brain Development and Function

Thyroid hormones are essential for brain developat through specific time windows influencing neurogenesis, neuronal migration, neuronal and glial cell differentiation, myelination, and synaptogenesis. The actions of thyroid hormones are mostly due to interaction of the active hormone T3 with nuclear receptors and regulation of gene expression. T4 and T3 also perform non-genomic actions. The genomically active T3 in brain derives in part from the circulation, and in part is formed locally by 5’-deiodination of T4, mediated by Dio2 in the astrocytes, in proportions that depend on the developmental stage. T4 and T3 are degraded by Dio3 present in neurons. Entry of T4 and T3 in brain is facilitated by specific transmembrane transporters, mainly the monocarboxylate transporter 8 (Mct8) and the organic anion transporter polypeptide 1c1 (Oatp1c1). In rodents Mct8 facilitates the transfer of T4 and T3 through the blood-brain barrier (BBB). Oatp1c1 transports T4 through the BBB and into to the astrocytes facilitating the generation of T3 in these cells. Primates have low amounts of OATP1C1 in the BBB, and depend of MCT8 for thyroid hormone transport. Therefore MCT8 mutations in humans cannot be compensated by T4 transport as in rodents. The thyroid hormone receptor subtypes TRα and TRβ are expressed throughout the brain from early development, and mediate overlapping actions on gene expression. However there are also TR-subtype specific actions. Dio3 for example is induced by T3 specifically through TRα1. In vivo T3 regulates gene expression during development from fetal stages, and in adult animals. A large number of genes are under direct and indirect regulation by thyroid hormone. In neural cells T3 may control around 5% of all expressed genes, and as much as one third of them may be regulated directly at the transcriptional level. Thyroid hormone deficiency during fetal and postnatal development may cause retarded brain maturation, intellectual deficits and in some cases neurological impairment. Thyroid hormone deficiency to the brain during development is caused by iodine deficiency, congenital hypothyroidism, and maternal hypothyroidism and hypothyroxinemia. The sydromes of Resistance to Thyroid Hormones due to receptor mutations, especially TRα, cause variable affectation of brain function. Mutations in the monocarboxylate transporter 8 cause a severe retardation of development and neurological impairment, likely due to deficient T4 and T3 transport to the brain. A challenge for the immediate future is a deep understanding of the pathophysiology of these syndromes, under the light of ample knowledge on thyroid hormone action in the brain, to allow designing appropriate therapies. For complete coverage of this and related areas in Endocrinology, please visit our free web-book, www.endotext.org.