SERINC1-dependent lipid preservation gates neocortical synaptogenesis and remote memory

Systems memory consolidation reorganizes episodic memories from the hippocampus into neocortical networks such as the anterior cingulate cortex (ACC), yet the localized molecular programs supporting this process remain unknown. Here, we show that the transmembrane lipid regulator Serinc1 is selectively induced in the ACC during neocortical memory consolidation. Loss of Serinc1 reduces ACC synapse density, blocks learning-induced de novo callosal synaptogenesis, and selectively abolishes remote memory. Lipidomic profiling reveals that SERINC1 prevents activity-dependent depletion of inner-leaflet anionic phospholipids—specifically docosahexaenoic acid (DHA) bearing-phosphatidylserine and arachidonic acid (AA) bearing-phosphatidylinositol—safeguarding signaling cascades required for structural plasticity. Targeted viral restoration of SERINC1 in the ACC rescues cortical synapse density and remote memory. Thus, long-term memory is gated by a localized program of activity-dependent neuro-lipidomic remodeling.