Thyroid Hormones, T3 and T4, 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 TRα1 and TRβ1, 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 TRα1 generally more responsive to T(4) than TRβ1. TRα1 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 TRα1 is well-established as the predominant isoform in brain, and that TRα1 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.