Abstract
Preclinical studies suggest that repeated exposure to anesthetics during a critical period of neurodevelopment induces long-term changes in synaptic transmission, plasticity, and behavior. Such changes are of great concern, as similar changes have also been identified in animal models of neurodevelopmental disorders (NDDs) such as autism. Because of overlapping synaptic changes, it is also possible that anesthetic exposures have a more significant effect in individuals diagnosed with NDDs. Thus, we evaluated the effects of early, multiple anesthetic exposures in BTBR mice, an inbred strain that displays autistic behavior. We discovered that three cycles of sevoflurane anesthesia (2.5%, 1 h) with 2-h intervals between each exposure in late postnatal BTBR mice did not aggravate, but instead improved pathophysiological mechanisms involved with autistic behavior. Sevoflurane exposures restored E/I balance (by increasing inhibitory synaptic transmission), and increased mitochondrial respiration and BDNF signaling in BTBR mice. Most importantly, such changes were associated with reduced autistic behavior in BTBR mice, as sociability was increased in the three-chamber test and repetitive behavior was reduced in the self-grooming test. Our results suggest that anesthetic exposures during neurodevelopment may affect individuals diagnosed with NDDs differently.
Highlights
Recent clinical studies agree that anesthetic exposure in young children does not affect general cognition, several studies have suggested significant changes in specific developmental domains such as motor and social performance (Warner et al, 2018; Walkden et al, 2020; Ing et al, 2021)
As we previously reported that sevoflurane exposures induce long-lasting E/I imbalance (Ju et al, 2020a), changes in E/I balance were evaluated by measuring spontaneous synaptic transmission in pyramidal neurons of the medial prefrontal cortex (mPFC), a brain region involved in autism behavior (Chung et al, 2015; Kim et al, 2016)
We discovered that inhibitory synaptic transmission was decreased in BTBR mice, as shown by a significant decrease in spontaneous inhibitory postsynaptic currents (sIPSCs) amplitude and frequency compared with B6 mice (Figures 1C,D) (Amplitude, Kruskal–Wallis test with post hoc Dunn’s test, p = 0.004; Frequency, analysis of variance (ANOVA) with post hoc Tukey’s HSD test, p < 0.001)
Summary
Recent clinical studies agree that anesthetic exposure in young children does not affect general cognition, several studies have suggested significant changes in specific developmental domains such as motor and social performance (Warner et al, 2018; Walkden et al, 2020; Ing et al, 2021). Short sevoflurane exposure (Chung et al, 2017a), multiple sevoflurane exposures induced long-lasting changes in synaptic transmission, plasticity, and behavior (Ju et al, 2020a). It should be noted that the neurotoxic effects of early, multiple anesthetic exposures have only been evaluated in normal mice (common inbred strains), but not in animal models of NDDs. Given the overlapping synaptic changes (E/I imbalance) observed in anesthesia-exposed animals and animal models of NDDs, it is possible that individuals with NDDs are more vulnerable to the neurotoxic effects of general anesthesia. Unlike the overall population, where repeated anesthetic exposures may induce subtle changes, it is possible that patients with preexisting cognitive impairments because of an E/I imbalance are at a higher risk due to the synergic effects of multiple anesthetic exposures
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