Deiodinase 3 Deficiency Impairs Hippocampal and Lateral Ventricle Neurogenesis in Middle-Aged Female Mice

Thyroid hormone (TH, the active metabolite T₃)) plays a critical role in neuronal proliferation and differentiation during development. However, its role in adult neurogenesis (ANG) remains incompletely understood. To gain insight into the role of T3 in ANG, we used a mouse model (Dio3KO mouse) with a deficiency in type 3 deiodinase, which clears T3 in the brain. We observed that the number of DCX/RBFOX3 double-positive cells is significantly reduced in the subgranular zone (SGZ) and the subventricular zone (SVZ) of 10-month-old female Dio3KO mice, suggesting impaired ANG in these neurogenic niches. However, no significant changes were observed in IBA1/GFAP or OLIG2/GFAP double-positive cells, suggesting that the neurogenic deficits are not associated with neuroinflammation, gliosis, or altered oligodendrogenesis. Cortical RNA-seq analysis further identified dysregulated T3-responsive genes implicated in ANG, revealing marked sex-dependent differences in gene expression. Proof-of-concept experiments in type 2 deiodinase 2 (Dio2) and Dio3 double knockout mice revealed a rescue of the neurogenic phenotype, supporting the hypothesis that loss of DIO2-mediated T3 generation counteracts the detrimental effects of DIO3 deficiency on ANG. Collectively, these findings identify DIO3- and DIO2-me fotmdiated T3 homeostasis in neural cells as critical contributors to T3-dependent ANG in females, with implications for neurodegenerative diseases and their sexually dimorphic prevalence.