Suppressing neural stem cell PLA2G7 restores inhibitory circuit function and improves cognition in aging mice.

Age-related cognitive decline is associated with altered inhibitory signaling in hippocampal circuits, but the mechanisms underlying this dysfunction remain incompletely understood. Neural stem cells (NSCs) persist in the adult hippocampus and influence brain function beyond generating new neurons, although the molecular signals involved remain unclear. Here we show that phospholipase A2 group VII (PLA2G7), a secreted lipid-metabolizing enzyme expressed in NSCs, negatively regulates inhibitory circuit function in the dentate gyrus. Conditional deletion of Pla2g7 in NSCs enhanced inhibitory inputs onto dentate granule cells and improved hippocampal cognition. Lipidomic profiling revealed PLA2G7-dependent remodeling of phospholipid composition, linking NSC-derived lipid metabolism to inhibitory synaptic regulation. Supplementation with phosphatidylcholine rescued PLA2G7-associated inhibitory synapse deficits. In aged mice, PLA2G7 suppression restored inhibitory circuit function, partially normalized circuit imbalance and improved cognition. These findings identify a non-neurogenic mechanism through which NSCs modulate hippocampal circuits and suggest PLA2G7 as a target for promoting cognitive function during aging.