Targeting the SIRT6–TDO2/KYNA–mTOR axis rescues synaptic and cognitive deficits in fetal growth restriction offspring

Fetal growth restriction (FGR), a major perinatal complication, is causally linked to lifelong cognitive deficits in offspring; however, its underlying mechanisms remain poorly defined. Here, the SIRT6–TDO2/KYNA–mTOR axis is identified as a critical mediator of synaptic dysfunction and cognitive deficits in FGR offspring. Hippocampal excitatory neurons in FGR mice exhibit markedly reduced SIRT6 expression, and SIRT6 conditional knockout in CaMKIIα⁺ neurons ( Sirt6 cKO) recapitulates FGR-induced synaptic and cognitive impairments. Mechanistically, SIRT6 governs synaptic plasticity and cognition via its histone deacetylase activity, independent of its ADP-ribosyltransferase function. SIRT6 deficiency increases histone H3K9 acetylation at the Tdo2 promoter, enhancing kynurenine pathway flux and leading to pathological accumulation of hippocampal kynurenic acid (KYNA). Elevated KYNA suppresses AKT/mTOR/p70S6K1 signaling, disrupting synaptic protein synthesis. Strikingly, pharmacological TDO2 blockade, neuronal TDO2 knockdown or mTOR activation reverses synaptic and cognitive deficits in Sirt6 cKO mice. Crucially, hippocampal SIRT6 overexpression in FGR mice normalizes KYNA levels, reactivates mTOR signaling, and restores synaptic plasticity and cognitive performance. These findings uncover a neurodevelopmental axis wherein neuronal SIRT6 deficiency dysregulates tryptophan metabolism to impair synaptic plasticity, identifying actionable targets for treating FGR-induced cognitive disorders. The alternative text for this image may have been generated using AI.