Unliganded thyroid hormone receptor alpha1 impairs adult hippocampal neurogenesis

摘要

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 bromo-deoxyuridine (BrdU)-positive 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-positive 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 rescued by thyroid hormone treatment, as was the decline in neuronal differentiation seen in the TRα1+/m mice. These mice also exhibited a decrease in NeuroD-positive cell numbers in the dentate gyrus, suggesting an effect on early postmitotic progenitors. Our results provide the first evidence of a role for unliganded TRα1 in modulating the deleterious effects of hypothyroidism on adult hippocampal neurogenesis.