Loss of microglial ATM drives synaptic pruning and cognitive impairment in epilepsy.

Microglia are the resident immune cells of the central nervous system, highly sensitive to oxidative stress and essential for maintaining synaptic homeostasis. While epilepsy induces profound redox imbalance, how oxidative stress reshapes microglial function and disrupts synaptic integrity remains unclear. Here we show that epileptic seizures drive early loss of ataxia-telangiectasia mutated (ATM) protein in microglia, independent of canonical DNA damage responses. ATM deficiency shifts microglia into a hyperphagocytic state, with morphological activation and aberrant synaptic engulfment. Single-nucleus transcriptomic analysis of human temporal lobe epilepsy samples reveals that microglial subpopulations with reduced ATM expression display transcriptional signatures of activation, enhanced lysosomal processing, and synapse remodeling, accompanied by extensive rewiring of ligand-receptor interactions with neurons. Restoring ATM in microglia attenuates aberrant phagocytic activity and rescues synaptic integrity and cognitive function. Mechanistically, ATM sustains CREB phosphorylation to maintain G6PD-dependent NADPH production and antioxidant capacity, the disruption of which precipitates mitochondrial oxidative injury and excessive microglial synaptic pruning. Together, our findings reveal a DNA damage-independent ATM-CREB-G6PD axis that limits oxidative stress and maladaptive microglial phagocytosis, highlighting ATM loss as a key driver of synaptic pathology in epilepsy.