Abstract TP081: Early IL2RA-Driven GRIN1 Lactylation Bridges Acute Excitotoxicity to Chronic Cognitive Decline After Stroke

Background: Post-stroke cognitive impairment (PSCI) affects over half of survivors within 6 months. The mechanistic link between acute excitotoxic stress and chronic synaptic degeneration remains unclear. We examined whether interleukin-2 receptor alpha (IL2RA) regulates hippocampal glutamate–glutamine (Glu/Gln) metabolism via GRIN1 lysine lactylation, driving long-term deficits. Methods: Male C57BL/6J mice underwent transient middle cerebral artery occlusion (MCAO) or sham surgery. Hippocampal neurotransmitters were quantified at 24h (UPLC-MS/MS). IL2RA interactors were identified by immunoprecipitation–mass spectrometry (IP-MS) and STRING. GRIN1 lactylation was predicted in silico, validated by IP-Kla-WB and mass spectrometry, and modulated by AAV-mediated IL2RA overexpression/knockdown in vivo and in primary neurons. Glu/Gln ratio, synaptic proteins, and lactylation levels were measured. Barnes maze and novel object recognition (NOR) assessed cognition at 28d post-MCAO. Results: At 24h post-MCAO, hippocampal glutamate increased by ~75%, glutamine decreased by ~40%, and the Gln/Glu ratio dropped by ~65% (p