Lithium attenuates ketamine-induced long-term neurotoxicity through DISC1-mediated GSK-3β/β-catenin and ERK/CREB pathways.

Ketamine, an antagonist of N-methyl-D-aspartate receptor, is extensively employed in pediatric anesthesia. Multiple studies have shown that repeated ketamine exposure induces neuroapoptosis, synaptic changes and cognitive deficits during neurodevelopment. Therefore, it is essential to elucidate the mechanisms of ketamine-induced neurotoxicity and develop therapies to mitigate its harmful effects. Here, we investigated the role of disrupted in Schizophrenia 1 (DISC1) in ketamine-induced long-term neurotoxicity through a ketamine-exposed neuroapoptosis model. Neonatal rats received 2-5 intraperitoneal injections of ketamine (20 mg/kg b.w.) at 90 min intervals. Another cohort of pups received five intraperitoneal injections of ketamine (20 mg/kg×5 b.w.) with or without lithium (120 mg/kg×5 b.w.) at 90 min intervals over 6 h. Neuroapoptosis, DISC1-associated proteins expression in rats treated with ketamine, lithium, or a combination of both were detected, and the cognitive function of adolescent rats was evaluated by Morris water maze test. The length of dendrites and axons of primary neurons treated with lithium and ketamine were further measured. Results showed that ketamine time-dependently downregulated the levels of DISC1, pGSK-3β, β-catenin, pERK, pCREB and PSD95 in neonatal rats. Lithium could ameliorate neuroapoptosis, cognitive deficits and neurite growth inhibition triggered by ketamine. Mechanistically, lithium upregulated the levels of DISC1, PSD95 and GSK-3β/β-catenin and ERK/CREB signaling-related proteins. Consequently, lithium mitigated ketamine-induced long-term neurotoxicity by elevating DISC1 level and activating the GSK-3β/β-catenin and ERK/CREB signaling pathways.