Sevoflurane, but not alphaxalone, causes lasting autism spectrum disorder-like pathology in male mice after exposure occurs during synaptogenesis.

Abstract

BACKGROUND AND PURPOSE: Early-life general anesthesia (GA) may cause changes in socio-emotional behaviors in animals and autism spectrum disorder (ASD) in humans. The mechanisms behind GA-induced ASD symptoms are unknown. We investigate the mTOR activation as a potential cause of ASD. We assess ASD-like pathology after neonatal GA exposure to a volatile agent, sevoflurane, or an injectable GA, alphaxalone. EXPERIMENTAL APPROACH: We exposed male mouse pups on postnatal day 7 (PND7) to sevoflurane or alphaxalone (and their respective vehicles) for 6 h. We performed histomorphological analysis of caspase-3 activity in subiculum 2 h post-GA exposure and Western blot analysis of mTOR activation in hippocampus 24 h post-GA exposure. Spike firing in thalamic neurons was assessed at 4-6 weeks post-GA exposure. Behavioral tests for ASD-like features, including ultrasonic vocalization (USV) at PND8, nestlet shredding, marble burying, and 3-chamber social tests were conducted in adulthood. KEY RESULTS: Sevoflurane, unlike alphaxalone, induced more nestlet shredding/marble burying compared to controls, and caused a shift away from the social preference and towards inanimate object. USV suggested a reduction in ultrasonic calls after sevoflurane, but not alphaxalone. The behavioral changes with sevoflurane were accompanied by an increase in caspase-3 activation, hyperactivation of mTOR, and an increase in neuronal firing compared to controls. The sevoflurane effects were largely reversed with rapamycin (a negative modulator of mTOR). CONCLUSION AND IMPLICATIONS: Unlike sevoflurane, alphaxalone does not cause long-lasting ASD-type behaviors and does not affect the mTOR activation and histomorphology, suggesting that alphaxalone could be a safer alternative to sevoflurane.