ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Neuropharmacology
Compensatory Attenuation of Cortical Apoptosis by SK2 Downregulation Following Ketamine Anesthesia
San Huang 1,2
Li Li 1
Yajuan Wang 1
Xu Ming 1
Yingwei Wang 1
Qi Wang 1
1. Department of Anesthesiology, Huashan Hospital, Fudan University, Shanghai, China
2. Department of Anesthesiology, Affiliated Hospital of North Sichuan Medical College, Sichuan, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Abstract
Introduction: A single exposure to general anesthetic can induce acute increase in neuronal apoptosis of the neonatal brain; however, how the brain counteracts the anesthetic-induced neurotoxicity remains unknown. The aim of this study is to explore how the neonatal cerebral cortex responds to anesthetic-induced neuronal apoptosis and the underlying mechanisms involved. Materials and Methods: Postnatal day 7 rats received intraperitoneal ketamine injections. Apoptotic neurons in the primary somatosensory cortex (S1) were quantified via immunohistochemistry. Whole-cell patch-clamp recordings were performed to assess neuronal activity of pyramidal neurons, including small conductance Ca²⁺-activated potassium (SK) channel-mediated medium afterhyperpolarization (mAHP) currents and spike frequency. SK2 expression was analyzed via Western blot, with genetic manipulation (overexpression/knockdown) to investigate its role in apoptosis regulation. SK2 ubiquitination and the ubiquitin-proteasome system (UPS) involvement were probed by co-immunoprecipitation and proteasomal inhibitor MG132. Results: Ketamine induced an acute surge in S1 neuronal apoptosis (mean ± SEM, control vs. ketamine, 1386.11 ± 253.63 /mm3 vs. 2229.07 ± 239.78 /mm3, P = 0.0247), followed by a significant reduction at 24 hours post-anesthesia (1281.35 ± 316.07 /mm3 vs. 554.24 ± 59.43 /mm3, P = 0.0417). This compensatory anti-apoptotic response coincided with attenuated SK channel-mediated mAHP currents (487.33 ± 38.00 pA vs. 355.33 ± 23.49 pA, P = 0.0058), which consequently enhanced neuronal spike frequency. Concurrently, both total (0.75 ± 0.04, P = 0.0156) and surface (0.76 ± 0.02, P = 0.0078) expression of SK2 channels were decreased in S1. SK2 overexpression reversed elevated neuronal excitability and blocked apoptotic reduction, while SK2 knockdown mimicked the pro-excitability and anti-apoptotic effects. SK2 downregulation relied on UPS-dependent degradation: MG132 restored SK2 levels, normalized spike frequency, and inhibited apoptotic reduction. Conclusions: The developing cortex compensates for ketamine-induced neuronal apoptosis by suppressing subsequent physiological apoptosis. This anti-apoptotic response is critically mediated by increased neuronal activity, driven by UPS-dependent SK2 downregulation.
Summary
Keywords
compensatory mechanisms3, ketamine1, neuronal apoptosis2, SK channe4, ubiquitin-proteasome system5
Received
05 December 2025
Accepted
20 February 2026
Copyright
© 2026 Huang, Li, Wang, Ming, Wang and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yingwei Wang; Qi Wang
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.