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Instituto de Investigaciones Biomédicas 28029 Madrid, Spain
Address all correspondence and requests for reprints to: Prof. Juan Bernal, Instituto de Investigaciones Biomédicas, Arturo Duperier 4, 28029 Madrid, Spain.
The developing brain is an important target of thyroid hormones. A complex regulatory network involving transfer of thyroid hormones through the brain barriers, interactions between neurons and glial cells, and deiodinase expression, works to deliver the appropriate amount of T3 to the nuclear receptors. The data provided by Heuer et al. (1) in this issue indicates that specific thyroid hormone transporters may also be an essential part of this regulatory system.
Thyroid hormones influence brain development from about the end of the first trimester of fetal life. The human fetal brain expresses nuclear T3 receptors at least from the 10th week of gestation, and receptor concentration increases 10-fold during the second trimester in brain and other tissues (2). T4 is present in brain and other tissues, such as liver, kidney, and lung, but T3 is detectable only in brain, at concentrations that result in an occupancy of brain T3 receptors around 25%. The source of T4 reaching the fetal brain up to midgestation is mostly of maternal origin (3). Both T4 and T3 cross the placenta and reach the fetal organs, but only T4 appears to cross the fetal blood-brain barrier. Thus, the administration of T3 by constant infusion to pregnant rat dams increased T3 concentrations in all maternal and fetal tissues except the fetal brain (4). In contrast, the administration of T4 increased T3 content in fetal brain as well as in other tissues. There was also a very important difference between the brain and the rest of the tissues. When increasing amounts of T4 were administered to pregnant dams maintained on methimazole, normal concentrations of T3 in the fetal brain were kept over a much wider range of T4 doses than in other tissues.
In adult rats, both T4 and T3 reach the brain from blood, but it was estimated that as much as 80% of the T3 bound to the nuclear receptors was produced locally by type 2 deiodinase (D2) activity (5). As in fetal brain, when either T4 or T3 was administered to hypothyroid rats, the T3 content of the brain was maintained within control values only by T4, but not by T3, infusion (6). Homeostasis of T3 within the brain is maintained within narrow limits by a complex mechanism involving D2 and D3. Several years ago we reported that D2 was predominantly expressed in glial cells of two types, tanycytes and astrocytes (7) (Fig. 1
). Tanycytes, in which expression of D2 was also reported by Tu et al. (8), are specialized ependymal cells lining the third ventricle and extending processes to the adjacent hypothalamus and the median eminence. The T3 generated by these cells from cerebrospinal T4 could play a role in TRH-TSH regulation. On the other hand, expression of D2 in the astrocytes suggested to us the existence of interplay between astrocytes and neurons on T3 homeostasis similar to the metabolic coupling between the two cells concerning the glutamate-glutamine cycle or glucose use (9). Astrocytes would produce T3 for neuronal use. As an additional control of neuronal T3 concentration, D3, which degrades T3 to the inactive metabolite diiodothyronine, is expressed in neurons. In this issue, Heuer et al. (1) confirm expression of D2 in the astrocytes and suggest important roles in T3 homeostasis for recently characterized thyroid hormone transporters (Fig. 1).
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Among the many members of the OATP family, human OATP-F (12) and rat Oatp14 (13) are preferentially expressed in brain. The Oatp14 protein is localized in the border of brain capillary endothelial cells and in the choroid plexus. OATP-F/Oatp14 transports T4 and rT3 much more efficiently than T3, and might be involved in the transport of T4 through the blood-brain barrier and through the choroid plexus, and also in rT3 clearance. The blood-brain barrier is the route by which thyroid hormone is preferentially distributed throughout the brain, and this transporter could facilitate uptake of T4 by the astrocytes. Transfer of thyroid hormone through the choroid plexus achieves only limited diffusion to the brain parenchyma after passage to the cerebrospinal fluid but would allow uptake of T4 by tanycytes and subsequent T3 generation in these cells.
The MCT family comprises up to 14 members, some of which are involved in the transport of important substrates for the brain such as lactate and pyruvate. MCT8 has been shown to act as a specific transporter for T4 and T3 and displays slightly higher affinity for T3 (14). Heuer et al. (1) have also studied the regional expression of MCT8 mRNA. In addition to high expression levels in the choroid plexus, they found that MCT8 is expressed in neurons of the neocortex, hippocampus, basal ganglia, amygdala, hypothalamus, and the Purkinje cells of the cerebellum, all regions known to be sensitive to thyroid hormones (15). Expression of MCT8 in neurons suggests that neuronal uptake of the T3 produced in astrocytes is facilitated by this transporter.
The physiological significance of MCT8 as a transporter for thyroid hormone is supported by the finding of mutations in humans by Dumitrescu et al. (16) and Friesema et al. (17). The syndrome affects children from an early age and consists of severe developmental delay and neurological damage together with an unusually altered pattern of thyroid hormone levels in blood. The patients presented low total and free T4, high total and free T3, and low rT3. TSH was moderately elevated in two of the patients and normal or slightly elevated in the other five. Inactivating mutations of the MCT8 transporter could result in the altered thyroid hormone levels. In vitro uptake of T4 and T3 by fibroblasts isolated from affected males was strongly reduced, and intracellular D2 was increased 6- to 8-fold (17). It is thus hypothesized that the resulting increase in intracellularly generated T3 accumulates in blood because of its poor reuptake into cells. In addition, deficient uptake of T4 and T3 by neurons could reduce degradation by neuronal D3 to rT3 and diiodothyronine, respectively, with increased T3 and decreased rT3. The brain and skin are predominant sites of D3 expression, but their contribution to T3 degradation and to blood rT3 is difficult to estimate (18).
The neurological syndrome caused by MCT8 mutations consists of developmental delays, rotary nystagmus, severe proximal hypotonia with poor head control, spastic quadriplegia, dystonic movements, and impaired gaze and hearing. More recently, a syndrome of paroxysmal dyskinesia has been recognized by Brockmann et al. (19) in the two patients originally described by Dumitrescu et al. (16). The whole clinical picture is so severe that it is pertinent to ask the question of whether the impaired uptake and action of thyroid hormone on neurons could cause such a syndrome. The neurological disorder of endemic cretinism (neurological cretinism) consists of variable degrees of neuromotor affectation with proximal limb girdle spasticity and rigidity, more often affecting the lower extremities, extrapyramidal disorders of rigidity and bradykinesia, deaf-mutism, strabismus, dysarthria, and mental deficiency (20). Epidemiological and physiopathological considerations indicate that this syndrome is most probably a result of lack of thyroid hormone during fetal development, especially before midgestation. This is the period of neuroblast proliferation and maturation of the basal ganglia and cerebral cortex. In the postmortem examination of the maternal uncle of one of the patients, also probably affected, loss of neurons in the cerebral cortex, basal ganglia, and cerebellum was found (16). As mentioned above, the second trimester is also the period when thyroid hormone receptors increase in concentration in the brain. If MCT8 is needed at this stage of development for T3 entry into neurons, mutations of the transporter could also interfere with T3-dependent developmental processes. Knowledge of the ontogenetic patterns of MCT8 in the human fetal brain would certainly be helpful. On the other hand, there is also the possibility that MCT8 mutations interfere with transport of other substrates for brain metabolism that could be even more important than T3 in determining the severity and outcome of the syndrome. Other members of the family transport metabolic substrates such as pyruvate and lactate, but MCT8 so far appears to be specific for iodothyronines (14).
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Received February 2, 2005.
Accepted for publication February 4, 2005.
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