Interval-dependent neurotoxicity after multiple ketamine injections in late postnatal mice

• Published in: Journal of anesthesia Vol. 35; no. 1; pp. 93 - 101
• Main Authors: Lee, Yulim, Youn, Ann Misun, Ju, Xianshu, Cui, Jianchen, Hong, Boohwi, Yun, Sangwon, Ko, Youngkwon, Kim, Yoon Hee, Heo, Jun Young, Chung, Woosuk
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 01.02.2021; Springer
• Subjects: Anesthesiology; Animals; Critical Care Medicine; Emergency Medicine; Female; Hippocampus; Intensive; Ketamine - toxicity; Male; Medicine; Medicine & Public Health; Mice; Original Article; Pain Medicine; Pyramidal Cells; Sevoflurane; Synaptic Transmission; South Korea; CA1 region; Anesthesia; Hippocampal; Ketamine; Synaptic transmission; Neurotoxicity syndromes
• ISSN: 0913-8668; 1438-8359
• DOI: 10.1007/s00540-020-02876-7

Purpose Measuring the neurotoxic effects of multiple anesthetic exposures during neurodevelopment is complex due to the numerous factors that can affect the outcome. While we recently discovered that the interval between multiple sevoflurane exposures can affect the level of neurotoxicity, the significance of interval for other anesthetic agents is unknown. Thus, we evaluated the significance of dosing interval in the neurotoxic effects of multiple ketamine injections in postnatal day (PND) 17 mice. Methods PND17 mice of both sexes were intraperitoneally injected with ketamine (35 mg/kg) three times at short (2 h) or long (24 h) intervals. Changes in synaptic transmission were measured in hippocampal pyramidal neurons 5 days after the last injection, and behavioral changes were assessed at the age of 8 weeks. Values are presented as mean ± SD. Results Whereas short-interval ketamine injections enhanced excitatory synaptic transmission, as evidenced by an increased frequency of miniature excitatory postsynaptic currents (mEPSCs; ketamine, 0.09 ± 0.07 Hz; control, 0.06 ± 0.03 Hz), long-interval ketamine injections did not; instead, they decreased the amplitude of miniature inhibitory postsynaptic currents (mIPSCs; ketamine, 47.72 ± 6.90 pA; control, 51.21 ± 7.65 pA,). However, only long-interval ketamine injections induced long-term changes in anxiety behavioral in the open-field test (decrease in center duration; ketamine, 400.1 ± 162.8 s; control, 613.3 ± 312.7 s). Conclusions Multiple ketamine injections induce interval-dependent, long-lasting synaptic changes and behavioral impairments. Future studies should carefully consider the dosing interval as a significant factor when studying the neurotoxic effects of multiple anesthetic exposures.