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To determine whether GM1 exerted its effect via the PI3K/AKT/GSK3β pathway, PC12 cells were incubated with LY294002, a PI3K inhibitor. We found that GM1 protected against ketamine-induced apoptosis in the hippocampus and cortex by reducing the expression of Bcl-2 and Caspase-3, and by increasing the expression of Bax. GM1 treatment increased the expression of p-AKT and p-GSK3β. However, the anti-apoptotic effect of GM1 was eliminated after inhibiting the phosphorylation of AKT. We showed that GM1 lessens ketamine-induced apoptosis in