Increased Kcnq2 in the hippocampal contributes to esketamine-induced long-term cognitive dysfunction in neonatal mice

Background: Esketamine is increasingly used to induce general anesthesia in pediatric populations. However, its neurological effects on healthy individuals-especially during early developmental stages-remain a topic of ongoing debate. In particular, concerns persist regarding its impact on the developing brain at extreme ages. Furthermore, the molecular mechanisms underlying these effects have not yet been fully elucidated.

Methods: Neonatal mice on postnatal days (P) 8, 10, and 12 received intraperitoneal injections of either sodium chloride or esketamine. Cognitive performance was assessed beginning at P56 using the Novel Object Recognition and Morris Water Maze tests to evaluate recognition memory and spatial learning, respectively. Hippocampal tissue samples were harvested at P14, P28, and P56 to investigate changes in molecular biomarkers. To explore the mechanistic role of Kcnq2, pharmacological inhibition was achieved using the selective antagonist XE991, while genetic suppression was performed using an adeno-associated virus-mediated knockdown approach.

Results: Repeated esketamine exposure during early postnatal development led to significant hippocampal injury, including the downregulation of glutamatergic neuronal markers and the onset of persistent cognitive dysfunction in adolescent mice. These adverse outcomes were strongly associated with elevated expression of Kcnq2 in the hippocampus. Both pharmacological blockade and genetic knockdown of Kcnq2 effectively mitigated the esketamine-induced cognitive deficits. Western blotting further revealed that inhibition of Kcnq2 restored the phosphorylation levels of Akt1 and glycogen synthase kinase-3β, which were otherwise downregulated following esketamine exposure.

Conclusions: Our findings demonstrate that repeated esketamine administration during critical periods of brain development results in long-lasting cognitive impairments, which are mediated by the upregulation of Kcnq2 expression in the hippocampus. Mechanistically, activation of Kcnq2 appears to drive the dephosphorylation of key signaling molecules within the Akt1/GSK-3β pathway. This study provides compelling experimental evidence of the neurotoxic potential of esketamine in developing brains and identifies Kcnq2 as a novel therapeutic target for preventing anesthesia-related cognitive deficits in pediatric populations.

Cognitive impairments; Esketamine; Kcnq2; Kv7.2; hippocampus.