Unliganded thyroid hormone receptor 1 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 TR 1 in adult hippocampal neurogenesis, using mice harboring a TR 1 null allele (TR 1 / ), overexpressing TR 1 6-fold (TR 2 / ), and a mutant TR 1 (TR 1 ) with a 10-fold lower affinity to the ligand. While hippocampal progenitor proliferation was unaltered, TR 1 / 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 TR 1 /m and the TR 2 / mice, where the overexpressed TR 1 acts as an aporeceptor, showed a significant decline in surviving BrdU progenitors. TR 1 / and TR 2 / mice showed opposing effects on neurogenic markers like polysialylated neural cell adhesion molecule and stathmin. The decreased progenitor survival in the TR 2 / and TR 1 /m mice could be rescued by thyroid hormone treatment, as was the decline in neuronal differentiation seen in the TR 1 /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 unliganded TR 1 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. Unliganded thyroid hormone receptor 1 impairs adult hippocampal neurogenesis. FASEB J. 24, 000–000 (2010). www.fasebj.org