Thyroid hormones, T3 andT4, in the brain

Thyroid hormones (THs) are essential for fetal and post-natal nervous system development and also play an important role in the maintenance of adult brain function. Of the two major THs, T-4 (3,5,3',5'-tetraiodo-l-thyronine) is classically viewed as an pro-hormone that must be converted to T-3 (3,5,3'-tri-iodo-l-thyronine) via tissue-level deiodinases for biological activity. THs primarily mediate their effects by binding to thyroid hormone receptor (TR) isoforms, predominantly TR alpha 1 and TR beta 1, which are expressed in different tissues and exhibit distinctive roles in endocrinology. Notably, the ability to respond to T-4 and to T-3 differs for the two TR isoforms, with TR alpha 1 generally more responsive to T-4 than TR beta 1. TR alpha 1 is also the most abundantly expressed TR isoform in the brain, encompassing 70-80% of all TR expression in this tissue. Conversion of T-4 into T-3 via deiodinase 2 in astrocytes has been classically viewed as critical for generating local T-3 for neurons. However, deiodinase-deficient mice do not exhibit obvious defectives in brain development or function. Considering that TR alpha 1 is well-established as the predominant isoform in brain, and that TR alpha 1 responds to both T-3 and T-4, we suggest T-4 may play a more active role in brain physiology than has been previously accepted.