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 TR alpha 1 in adult hippocampal neurogenesis, using mice harboring a TR alpha 1 null allele (TR alpha 1(-/-)), overexpressing TR alpha 1 6-fold (TR alpha 2(-/-)), and a mutant TR alpha 1 (TR alpha 1(+/m)) with a 10-fold lower affinity to the ligand. While hippocampal progenitor proliferation was unaltered, TR alpha 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 alpha 1(+/m) and the TR alpha 2(-/-) mice, where the over-expressed TR alpha 1 acts as an aporeceptor, showed a significant decline in surviving BrdU(+) progenitors. TR alpha 1(-/-) and TR alpha 2(-/-) mice showed opposing effects on neurogenic markers like polysialylated neural cell adhesion molecule and stathmin. The decreased progenitor survival in the TR alpha 2(-/-) and TR alpha 1(+/m) mice could be rescued by thyroid hormone treatment, as was the decline in neuronal differentiation seen in the TR alpha 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 alpha 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 alpha 1 impairs adult hippocampal neurogenesis. FASEB J. 24, 4793-4805 (2010). www.fasebj.org