Unliganded thyroid hormone receptor αl impairs adult hippocampal neurogenesis

Abstract

Thyroid hormone regulates adult hippocampal neurogenesis’ a process involved in key functions’ such as learning’ memory’ and mood regulation. We addressed the role of thyroid hormone receptor TRαl in adult hippocampal neurogenesis’ using mice harboring a TRαl null allele (TRα1 –/– )’ overexpressing TRαl 6‐fold (TRα2 –/– )’ and a mutant TRαl (TRα1 +/m ) with a lO‐fold lower affinity to the ligand. While hippocampal progenitor proliferation was unaltered’ TRαl _/_ mice exhibited a significant increase in doublecortin‐positive immature neurons and increased survival of bromodeoxyuridine‐positive (BrdU + ) progenitors as compared to wild‐type controls. In contrast’ the TRαl +/m and the TRα2 –/– mice’ where the over‐expressed TRαl acts as an aporeceptor’ showed a significant decline in surviving BrdU + progenitors. TRαl”“ andTRα2 –/– mice showed opposing effects on neurogenic markers like polysialylated neural cell adhesion molecule and stathmin. The decreased progenitor survival in the TRα2 –/– and TRαl +/m mice could be rescued by thyroid hormone treatment’ as was the decline in neuronal differentiation seen in the TRαl +/m mice. These mice also exhibited a decrease in NeuroD + cell numbers in the dentate gyrus’ suggesting an effect on early postmitotic progenitors. Our results provide the first evidence of a role for unligan‐ded TRαl in modulating the deleterious effects of hypothyroidism on adult hippocampal neurogenesis.— Kapoor’ R.’ van Hogerlinden’ M.’ Wallis’ K.’ Ghosh’ H.’ Nordstrom’ K.’ Vennstrom’ B.’ Vaidya’ V. A. Unligan‐ded thyroid hormone receptor αl impairs adult hip‐pocampal neurogenesis. FASEB J. 24’ 4793–4805 (2OlO). www.fasebj.org