The impact of general anesthetics on brain development has been a cause for concern. Researchers conducted experiments using different anesthetic agents on cultured cortical cells and postnatal mice to investigate the shared signaling pathway responsible for the effects of anesthesia. They discovered that all anesthetic agents tested reduced phosphorylation of the ribosomal protein S6, a key player in the mTOR signaling pathway. This reduction in S6 phosphorylation leads to suppression of the mTOR pathway, which is crucial for neural circuit development. The findings suggest that this common signaling event may mediate the detrimental effects of anesthetics on brain wiring. Further research is needed to fully understand the implications and potential long-lasting cognitive impacts of these findings.

IntroductionThe development and maintenance of neural circuits is highly sensitive to neural activity. General anesthetics have profound effects on neural activity and, as such, there is concern that these agents may alter cellular integrity and interfere with brain wiring, such as when exposure occurs during the vulnerable period of brain development. Under those conditions, exposure to anesthetics in clinical use today causes changes in synaptic strength and number, widespread apoptosis, and long-lasting cognitive impairment in a variety of animal models. Remarkably, most anesthetics produce these effects despite having differing receptor mechanisms of action. We hypothesized that anesthetic agents mediate these effects by inducing a shared signaling pathway.MethodsWe exposed cultured cortical cells to propofol, etomidate, or dexmedetomidine and assessed the protein levels of dozens of signaling molecules and post-translational modifications using reverse phase protein arrays. To probe the role of neural activity, we performed separate control experiments to alter neural activity with non-anesthetics. Having identified anesthetic-induced changes in vitro, we investigated expression of the target proteins in the cortex of sevoflurane anesthetized postnatal day 7 mice by Western blotting.ResultsAll the anesthetic agents tested in vitro reduced phosphorylation of the ribosomal protein S6, an important member of the mTOR signaling pathway. We found a comparable decrease in cortical S6 phosphorylation by Western blotting in sevoflurane anesthetized neonatal mice. Using a systems approach, we determined that propofol, etomidate, dexmedetomidine, and APV/TTX all similarly modulate a signaling module that includes pS6 and other cell mediators of the mTOR-signaling pathway.DiscussionReduction in S6 phosphorylation and subsequent suppression of the mTOR pathway may be a common and novel signaling event that mediates the impact of general anesthetics on neural circuit development.

Read Full Article (External Site)