Objective To evaluate the role of hippocampal phosphatidylinositol 3-kinase/serinethreonine kinase/glycogen synthase kinase-3 beta (PI3K/Akt/GSK-3β) signaling pathway in dexmedetomidine-induced reduction of long-term cognitive decline caused by propofol in neonatal rats.Methods A total of 110 clean healthy male Sprague-Dawley rats,aged 7 days,weighing 10-15 g,were divided into 11 groups (n=10 each) using a random number table:normal saline group (NS group),fat emulsion group (F group),10％ dimethyl sulfoxide (DMSO) group (D2 group),dexmedetomidine group (DEX group),TDZD-8 group (TDZD group),10％ DMSO group (D1 group),LY294002 group (LY group),propofol group (P group),dexmedetomidine plus propofol group (PD group),LY294002 plus dexmedetomidine plus propofol group (LYPD group) and TDZD-8 plus dexmedetomidine plus propofol group (TDPD group).Normal saline,fat emulsion,10％ DMSO 100 μl,dexmedetomidine 75 μg/kg and TDZD-8 1 mg/kg were intraperitoneally injected in NS,F,D2,DEX and TDZD groups,respectively.10％ DMSO 5 μ1 and LY294002 25 μg/5 μl were injected via the lateral cerebral ventricle in D1 and LY groups,respectively.Propofol 50 mg/kg was intraperitoneally injected,and an increment of propofol 50 mg/kg was given after recovery of righting reflex in group P.Dexmedetomidine 75 μg/kg was intraperitoneally injected and 30 min later propofol was injected in group PD.LY294002 was injected,30 min later dexmedetomidine was injected,and 30 min later propofol was injected in group LYPD.In group TDPD,TDZD-8 was injected and the other treatment was similar to those previously described in group LYPD.Then the rats were fed to 9 weeks old after returning to the state of consciousness.Morris water maze test was performed to evaluate the cognitive function.Rats were then sacrificed and their hippocampi were harvested for detection of the expression of PI3K,Akt,GSK-3β and PSD95 mRNA (using real-time polymerase chain reaction) and expression of Akt,pAkt(ser473),GSK-3β,pGSK-3β(ser9) and PSD95 (by Western blot).Results Compared with NS group,the escape latency was significantly prolonged,the number of crossing the original platform was reduced,the expression of PI3K,Akt and PSD95 mRNA was down-regulated,the expression of GSK-3β mRNA was up-regulated,p-Akt(ser473)/Akt ratio was decreased,the expression of PSD95 was downregulated,and pGSK-3β (ser9)/GSK-3β ratio was increased in P group (P＜ 0.05).Compared with P group,the escape latency was significantly shortened and the number of crossing the original platform was increased in PD,LYPD and TDPD groups,the expression of PI3K,Akt and PSD95 mRNA was up-regulated,and the expression of GSK-3β mRNA was down-regulated in PD group,and pAkt(ser473)/Akt ratio was increased,the expression of PSD95 was up-regulated,and pGSK-3β (ser9)/GSK-3β ratio was decreased in PD and TDPD groups(P＜0.05).Compared with PD group,the escape latency was significantly prolonged,the number of crossing the original platform was reduced,the expression of GSK-3β mRNA was up-regulated,the expression of PSD95 mRNA was down-regulated,pAkt (ser473)/Akt ratio was decreased,the expression of PSD95 was down-regulated,and pGSK-3β (ser9)/GSK-3β ratio was increased in LYPD group,and the escape latency was significantly shortened,the number of crossing the original platform was increased,the expression of GSK-3β mRNA was down-regulated,the expression of PSD95 mRNA was up-regulated,pGSK-3β(ser9)/GSK-3β ratio was decreased,and the expression of PSD95 was up-regulated in TDPD group(P＜0.05).Conclusion Hippocampal PI3K/Akt/GSK-3β signaling pathway is involved in dexmedetomidine-induced reduction of long-term cognitive decline caused by propofol in neonatal rats.