TDG TUNES COGNITIVE FLEXIBILITY: LINKING DNA DEMETHYLATION TO ADAPTIVE MEMORY UPDATING

Memory formation and updating rely on activity-dependent transcriptional programs that reshape synaptic connectivity. These programs are regulated by dynamic DNA methylation and demethylation, which fine-tune chromatin accessibility. Thymine DNA glycosylase (TDG) is a key enzyme in active DNA demethylation, excising oxidized methylcytosines via the base excision repair (BER) pathway. Complete TDG loss is embryonic lethal, underscoring its essential role in early epigenetic regulation. It is unclear whether TDG also governs epigenetic plasticity and functional identity in mature neurons. To address TDG’s neuroepigenetic role in synaptic plasticity and memory, we generated a mouse model with a temporally controlled TDG depletion in hippocampal excitatory neurons, starting at p19, thereby circumventing embryonic lethality. TDG-deficient hippocampi accumulate oxidized methylcytosine substrates (5fC and 5caC), suggesting impaired restoration of unmethylated cytosine. Bulk RNA-seq revealed widespread transcriptional reprogramming of plasticity-related genes. Behaviorally, TDG-deficient mice exhibited normal fear memory acquisition and recall but showed reduced memory flexibility, including slower extinction and impaired cue discrimination. Together, these findings suggest that TDG is dispensable for initial memory formation but essential for adaptive updating of fear memories, highlighting a critical neuroepigenetic mechanism linking DNA repair to experience-dependent plasticity.