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Published on: May 12, 2015
Increased Kcnq2 in the hippocampal contributes to esketamine-induced long-term cognitive dysfunction in neonatal mice
Junjie Zhang1, Rui Xiong1, Yujuan Su1
1Department of Anesthesiology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, No. 136, Zhongshan Second Road, Chongging 400014, China; Chongqing Key Laboratory of Pediatrics, Chongqing, China.
Insights
Esketamine use in young children may cause lasting cognitive deficits by harming the hippocampus and increasing Kcnq2 expression. Targeting Kcnq2 could prevent these anesthesia-related brain effects.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Esketamine is used for pediatric anesthesia, but its effects on the developing brain are debated.
- Concerns exist regarding neurological impacts on young brains, especially at critical developmental stages.
- The molecular mechanisms behind esketamine's neurodevelopmental effects are not fully understood.
Purpose of the Study:
- To investigate the neurological effects of early-life esketamine exposure in neonatal mice.
- To elucidate the molecular mechanisms underlying esketamine-induced cognitive dysfunction.
- To identify potential therapeutic targets for mitigating anesthesia-related cognitive deficits.
Main Methods:
- Neonatal mice received esketamine or saline injections on postnatal days 8, 10, and 12.
- Cognitive functions (memory and spatial learning) were assessed in adolescence using behavioral tests.
- Hippocampal tissues were analyzed for molecular changes, including Kcnq2 expression and signaling pathways.
- Kcnq2 was pharmacologically inhibited (XE991) or genetically suppressed to assess its role.
Main Results:
- Repeated esketamine exposure caused hippocampal injury and persistent cognitive deficits in adolescent mice.
- Elevated hippocampal Kcnq2 expression was strongly associated with these adverse effects.
- Inhibiting Kcnq2 (pharmacologically or genetically) prevented esketamine-induced cognitive impairments.
- Kcnq2 inhibition restored Akt1/GSK-3β signaling pathway phosphorylation, which was downregulated by esketamine.
Conclusions:
- Early-life esketamine administration leads to long-lasting cognitive impairments mediated by hippocampal Kcnq2 upregulation.
- Kcnq2 activation drives dephosphorylation of Akt1/GSK-3β signaling molecules.
- This study highlights the neurotoxic potential of esketamine in developing brains and identifies Kcnq2 as a therapeutic target.
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.
