The SIRT6-TDO2/KYNA-mTOR Axis Mediates Synaptic Plasticity and Cognitive Impairments in Fetal Growth Restriction Offspring

Fetal growth restriction (FGR) can lead to cognitive impairment in offspring, but the underlying mechanisms remain unclear. This study found that hippocampal excitatory neurons in FGR mice exhibit significantly reduced SIRT6 expression. SIRT6 deficiency upregulates TDO2 via its histone deacetylase activity (independent of ADP-ribosyltransferase function), promoting kynurenic acid (KYNA) accumulation, which suppresses the AKT/mTOR/p70S6K pathway and disrupts synaptic protein synthesis. RNA-seg profiling of the hippocampus at 8 weeks in WT mice and Sirt6 cKO mice