Unliganded thyroid hormone receptor α1 impairs adult hippocampal neurogenesis

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 TRα1 in adult hippocampal neurogenesis, using mice harboring a TRα1 null allele (TRα1−/−), overexpressing TRα1 6-fold (TRα2−/−), and a mutant TRα1 (TRα1+/m) with a 10-fold lower affinity to the ligand. While hippocampal progenitor proliferation was unaltered, TRα1−/− 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 TRα1+/m and the TRα2−/− mice, where the overexpressed TRα1 acts as an aporeceptor, showed a significant decline in surviving BrdU+ progenitors. TRα1−/− and TRα2−/− mice showed opposing effects on neurogenic markers like polysialylated neural cell adhesion molecule and stathmin. The decreased progenitor survival in the TRα2−/− and TRα1+/m mice could be r...