Thyroid hormones,T3 andT4, in the brain

*Correspondence: Martin L. Privalsky , Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California Davis, One Shields Avenue, Davis, CA 95616, USA e-mail: mlprivalsky@ucdavis.edu 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,T4 (3,5,3,5-tetraiodo-l-thyronine) is classically viewed as an pro-hormone that must be converted toT3 (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, predominantlyTRα1 andTRβ1, which are expressed in different tissues and exhibit distinctive roles in endocrinology. Notably, the ability to respond toT4 and toT3 differs for the two TR isoforms, with TRα1 generally more responsive to T4 than TRβ1. TRα1 is also the most abundantly expressedTR isoform in the brain, encompassing 70–80% of all TR expression in this tissue. Conversion of T4 into T3 via deiodinase 2 in astrocytes has been classically viewed as critical for generating local T3 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 T3 and T4, we suggest T4 may play a more active role in brain physiology than has been previously accepted.