Unliganded thyroid hormone receptor alpha1 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 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(+/m)) 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.

SUBMITTER: Kapoor R 

PROVIDER: S-EPMC4177098 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature