Increasing the interval between repeated anesthetic exposures reduces long‐lasting synaptic changes in late post‐natal mice

Abstract

While recent studies strongly suggest that a single, short anesthetic exposure does not affect neurodevelopment, the effects of multiple exposures remain unclear. Unfortunately, studying “multiple exposures” is challenging as it is an extremely heterogeneous descriptor comprising diverse factors. One potentially important, but unrecognized factor is the interval between anesthetic exposures. In order to evaluate the significance of interval, we exposed post‐natal day 16, 17 mice to three sevoflurane exposures (2.5%, 1 hr) with short (2 hr) or long (24 hr) intervals. Changes in synaptic transmission, plasticity, protein expression, and behavior were assessed in male and female mice. We discovered that short‐interval exposures induced a female‐dependent decrease in miniature inhibitory post‐synaptic current (mIPSC) frequency 5 days after the last exposure (control: 18.44 ± 2.86 Hz, sevoflurane:14.65 ± 4.54 Hz). Short‐interval sevoflurane exposed mice also displayed long‐term behavioral deficits at adult age (hypoactivity, anxiety). These behavioral changes were consistent with the sex‐dependent changes in inhibitory transmission, as they were more robust in female mice. Although there was no change in learning and memory, short‐interval sevoflurane exposures also impaired LTP in a non‐sex‐dependent manner (control: 171.10 ± 26.90%, sevoflurane: 149.80 ± 26.48 %). Most importantly, we were unable to find long‐lasting consequences in mice that received long‐interval sevoflurane exposures. Our study provides novel insights regarding the significance of the interval between multiple exposures, and also suggests that the neurotoxic effects of multiple anesthetic exposures may be reduced by simply increasing the interval between each exposure.

General Anesthesia During Neurodevelopment Reduces Autistic Behavior in Adult BTBR Mice, a Murine Model of Autism

“…BTBR mice were exposed to sevoflurane at PND16/17 as previously described ( Ju et al, 2020a ). Mice were randomly divided into four groups: a naïve C57BL/6J (B6-control) group, a B6-sevoflurane group, a BTBR-control group, and a BTBR-sevoflurane group.…”

“…Western blot was performed as previously described ( Ju et al, 2020a ). Protein samples of the cerebral cortex were obtained 5 days after sevoflurane exposures.…”

“…Sample size was based on previous studies ( Chung et al, 2017a ; Ju et al, 2020a ). Data were analyzed using the R statistical software package (4.0.3; R Core Team, Austria).…”

“…Also, the neurotoxic effects of prolonged or multiple anesthetic exposures also remain undetermined. Preclinical animal studies, including those in rodents, sheep and non-human primates, strongly suggest that multiple anesthetic exposures, unlike a single exposure, may affect neurodevelopment ( Olutoye et al, 2016 ; Chung et al, 2017b ; Raper et al, 2018 ; Ju et al, 2020a ; Neudecker et al, 2021 ). Recent clinical studies also support a distinction between single and multiple anesthetic exposures, with the latter suggested to have long-term negative consequences ( Hu et al, 2017 ; Warner et al, 2018 ; Zaccariello et al, 2019 ).…”

“…Our group recently reported similar results of exposing postnatal day 16, 17 (PND16/17) mice to sevoflurane. Unlike a single, short sevoflurane exposure ( Chung et al, 2017a ), multiple sevoflurane exposures induced long-lasting changes in synaptic transmission, plasticity, and behavior ( Ju et al, 2020a ). Such long-lasting synaptic changes after multiple anesthetic exposures are of great concern, since excitatory/inhibitory (E/I) imbalance may act as an underlying mechanism of neurodevelopmental disorders (NDDs) ( Lee et al, 2017 ; Sohal and Rubenstein, 2019 ).…”