The thyroid hormones (THs) L-thyroxine (T4) and L-triiodothyronine (T3) have a profound influence on the development and maturation of the mammalian brain, both before and after birth. Any impairment in the supply of THs to the developing nervous system leads to severe and irreversible changes in both the overall architecture and functions of the brain and causes, in humans, neurological and motor deficits known as cretinism. Pronounced neurological symptoms are also commonly observed in adult patients suffering from both hyperthyroidism and hypothyroidism, and it has recently emerged that certain symptoms might result from the reduced brain uptake, rather than the insufficient production, of THs. Most of the effects of THs are mediated by two classes of nuclear receptors (α and β isoforms), which belong to the c-erbA superfamily of transcriptional regulators and are expressed in a tissue-specific and developmentally regulated manner. Interestingly, the nuclear TH receptors (nTRs) act as both ligand-independent gene repressors and ligand-dependent gene activators. On the other hand, negatively-regulated genes, which can be stimulated in the absence of THs and repressed by THs, have also been observed. Due to this complex pattern of regulation, the effects of receptor dysfunction do not exactly overlap the effects of hormone deficiency or excess. Moreover, non-genomic mechanisms of TH action have been described in many tissues, including the brain, some of which seem to be mediated by integrins and to be calcium-dependent. Intracellular receptors, distinct from nTRs, are present in the mitochondria, where a matrix-associated, T3-dependent transcriptional regulator of approximately 43 kDa has been described. Finally, complex patterns of pituitary and/or peripheral resistance to thyroid hormones (RTH), characterized by elevated plasma levels of THs and non-suppressible thyroid-stimulating hormone (TSH), have been identified. This review summarizes the major advances in knowledge of the molecular mechanisms of TH action and their implication for the effects of THs on the developing, as well as the adult mammalian, nervous system.

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