Finding the Way into the Brain without MCT8

Abstract

How does thyroid hormone (TH) find its way into the brain? Although it has been known for a long time that TH is crucial for normal brain development, the exact molecular mechanisms involved in TH transport in the brain have remained elusive until recently. Early studies showed selective and saturable accumulation of TH in particular brain regions, suggesting that active transport processes are required for TH entry across the blood-brain barrier (BBB) and into brain cells (1). The discovery that TH transporter proteins located in the plasma membrane are required for cellular entry of the hormone has advanced our understanding of TH physiology. Thus, TH transporters mediate transport not only across the BBB but also into each individual cell of the brain. Many transporters have been identified that accept a wide range of substrates, including TH (2). Monocarboxylate transporter 8 (MCT8) and its homolog, MCT10, are important exceptions, showing a high activity and specificity for TH (3, 4). MCT10 shows preference for T3 over T4, but also transports aromatic amino acids. MCT8 transports different iodothyronines (T4, T3, rT3, 3,3 -T2) with similar efficiencies but does not appear to transport aromatic amino acids. The biological importance of TH transporters was clearly established by the discovery of patients harboring mutations in the MCT8 gene, which is located on the Xchromosome (5, 6). Affected male patients suffer from severe psychomotor retardation and also show abnormal serum TH levels. They have severe cognitive deficits, with IQ values mostly below 40. Speech development is mostly severely hampered. Newborns with MCT8 mutations present with global hypotonia. The central hypotonia that is associated with poor head control persists throughout life, whereas the peripheral hypotonia usually progresses into spastic quadriplegia. Most patients are unable to sit, stand, or walk independently. Patients with MCT8 mutations demonstrate typical abnormal thyroid function tests. Serum T3 levels are elevated, and both serum T4 and rT3 levels are decreased. TSH levels range from normal to moderately elevated, with mean values twice that in controls. Because the clinical phenotype resembles that in subjects with the AllanHerndon-Dudley syndrome (AHDS), Schwartz et al. (7) discovered that mutations in MCT8 represent the genetic basis of this syndrome originally described in 1944. The pathogenicity of most mutations has been documented by assessing the TH transport capacity of the mutants by in vitro assays. The pathogenesis of the AHDS is incompletely understood. The current hypothesis holds that the brain of AHDS patients is deprived of TH and, thus, is in a hypothyroid state. This concept is based on the expression of MCT8 in the BBB, in the choroid plexus (blood-cerebrospinal fluid interface), and in neuronal cells (8). Myelination, which depends on TH, is delayed in AHDS patients, suggesting also an important role of MCT8 in oligodendrocytes. Unfortunately, Mct8 knockout (KO) mice lack overt neurological features, limiting the use of this model to study the pathogenesis of the neurological phenotype of AHDS patients (9, 10). Nevertheless, it has been clearly established that cerebral T3 and T4 levels are diminished in Mct8 KO mice. Available evidence suggests that brain T4 is low because of the low supply of serum T4, and not so much because of decreased T4 transport into the brain, whereas the low brain T3 despite the high serum T3 is caused by impaired T3 transport into the brain (11). The reduced cerebral TH levels in Mct8 KO mice still appear sufficient to support expression of T3 target genes and relatively normal brain development. Adaptive regu-