Thyroid hormones are important during development of the mammalian brain, acting on migration and differentiation of neural cells, synaptogenesis, and myelination. The actions of thyroid hormones are mediated through nuclear thyroid hormone receptors (TRs) and regulation of gene expression. The purpose of this article is to review the role of TRs in brain maturation. In developing humans maternal and fetal thyroid glands provide thyroid hormones to the fetal brain, but the timing of receptor ontogeny agrees with clinical data on the importance of the maternal thyroid gland before midgestation. Several TR isoforms, which are encoded by the THRA and THRB genes, are expressed in the brain, with the most common being TRalpha1. Deletion of TRalpha1 in rodents is not, however, equivalent to hormone deprivation and, paradoxically, even prevents the effects of hypothyroidism. Unliganded receptor activity is, therefore, probably an important factor in causing the harmful effects of hypothyroidism. Accordingly, expression of a mutant receptor with impaired triiodothyronine (T(3)) binding and dominant negative activity affected cerebellar development and motor performance. TRs are also involved in adult brain function. TRalpha1 deletion, or expression of a dominant negative mutant receptor, induces consistent behavioral changes in adult mice, leading to severe anxiety and morphological changes in the hippocampus.

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Thyroid hormone plays an essential role in mammalian brain maturation and function, in large part by regulating the expression of specific neuronal genes. In this tissue, the type 2 deiodinase (D2) appears to be essential for providing adequate levels of the active thyroid hormone 3,5,3-triiodothyronine (T3) during the developmental period. We have studied the regional and cellular localization of D2 mRNA in the brain of 15-day-old neonatal rats. D2 is expressed in the cerebral cortex, olfactory bulb, hippocampus, caudate, thalamus, hypothalamus, and cerebellum and was absent from the white matter. At the cellular level, D2 is expressed predominantly, if not exclusively, in astrocytes and in the tanycytes lining the third ventricle and present in the median eminence. These results suggest a close metabolic coupling between subsets of glial cells and neurons, whereby thyroxine is taken up from the blood and͞or cerebrospinal f luid by astrocytes and tanycytes, is deiodinated to T3, and then is released for utilization by neurons.Thyroid hormone controls a number of metabolic and developmental processes and, in particular, is an essential factor for normal mammalian brain maturation (1). In humans and other species, thyroid deficiency during the perinatal period results in irreversible brain damage and mental retardation (1, 2). The effects of thyroid hormone result primarily from changes in gene expression mediated through the binding of the active compound 3,5,3Ј-triiodothyronine (T3) to specific nuclear receptors of the steroid-retinoic acid-thyroid hormone superfamily. Previous studies have demonstrated that T3 nuclear receptors are expressed in a complex temporal pattern in specific regions of the brain that include the cerebral cortex, hippocampus, striatum, cerebellum, and hypothalamus (3, 4). These receptors are found predominantly in neurons and oligodendrocytes (5-7), and a number of neuronal genes have been shown to be regulated by thyroid hormone during development (8, 9).The majority of T3 in the brain is produced locally within the central nervous system by the 5Ј-deiodination of thyroxine (T4) (10). The type 2 deiodinase (D2) appears to be of particular importance in catalyzing the conversion of T4 to T3 in the brain during fetal and early neonatal life (11)(12)(13). During this period in the rat, the expression of D2 activity in brain increases at the end of gestation and is highest at 15-20 days of postnatal life (14). This pattern of activity corresponds temporally to the period when the developing brain is most dependent on thyroid hormone and correlates with increasing brain T3 concentrations, which peak at 2 weeks of age (13).An important property of the D2 is that its activity is markedly increased by thyroid hormone deficiency (15). This enhanced D2 activity serves to maintain T3 production in the brain in the face of limiting amounts of the prohormone T4 (16). Brain T3 levels thus appear to be protected to a considerable extent by alterations in circulating thyroid hormone levels (12...

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The purpose of this review is to provide an up-to-date report on the molecular and physiologic processes involved in the role of thyroid hormone as an epigenetic factor in brain maturation. We summarize the available data on the control of brain gene expression by thyroid hormone, the correlation between gene expression and physiologic effects, and the likely mechanisms of action of thyroid hormone on brain gene expression. In addition we propose a role for unliganded thyroid hormone receptors in the pathogenesis of hypothyroidism. Finally, we review recent data indicating that thyroid hormone receptors have an impact on behavior.

The cellular influx and efflux of thyroid hormones are facilitated by transmembrane protein transporters. Of these transporters, monocarboxylate transporter 8 (MCT8) is the only one specific for the transport of thyroid hormones and some of their derivatives. Mutations in SLC16A2, the gene that encodes MCT8, lead to an X-linked syndrome with severe neurological impairment and altered concentrations of thyroid hormones. Histopathological analysis of brain tissue from patients who have impaired MCT8 function indicates that brain lesions start prenatally, and are most probably the result of cerebral hypothyroidism. A Slc16a2 knockout mouse model has revealed that Mct8 is an important mediator of thyroid hormone transport, especially T3, through the blood-brain barrier. However, unlike humans with an MCT8 deficiency, these mice do not have neurological impairment. One explanation for this discrepancy could be differences in expression of the T4 transporter OATP1C1 in the blood-brain barrier; OATP1C1 is more abundant in rodents than in primates and permits the passage of T4 in the absence of T3 transport, thus preventing full cerebral hypothyroidism. In this Review, we discuss the relevance of thyroid hormone transporters in health and disease, with a particular focus on the pathophysiology of MCT8 mutations.