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<0.001), indicating marked metabolic imbalance. IL2RA expression was markedly elevated (~2.4-fold at 24h) in MCAO hippocampi and OGD/R neurons. IP-MS identified GRIN1, GLUL, and mTOR as major IL2RA interactors, with GO/STRING enrichment linked to glutamate metabolism and synaptic signaling pathways (FDR<0.05); Co-IP confirmed direct binding of IL2RA with GRIN1, GLUL, and mTOR. GRIN1 lactylation was upregulated (~1.5-fold after MCAO and ~2.7-fold after OGD/R, p<0.01). Mechanistically, IL2RA overexpression reduced HDAC3 expression, thereby further enhancing GRIN1 lactylation (+2.8-fold), while IL2RA knockdown restored HDAC3 levels and reduced lactylation by ~68%. At 28 days, IL2RA knockdown mice showed improved performance in Barnes maze and novel object recognition compared with MCAO alone, indicating that IL2RA modulation alleviates post-stroke cognitive deficits. Conclusions: IL2RA upregulation after stroke promotes GRIN1 lactylation through HDAC3 suppression, causing Glu/Gln imbalance, synaptic protein loss, and cognitive decline. This lactylation is initiated acutely and sustained chronically, bridging early excitotoxic injury to long-term impairment. Targeting the IL2RA–HDAC3–GRIN1 axis in the early window may prevent PSCI and provide a therapeutic strategy.