Human epidemiologic studies and laboratory investigations in animal models suggest\nthat exposure to general anesthetic agents (GAs) have harmful effects on brain development.\nThe mechanism underlying this putative iatrogenic condition is not clear and there are currently\nno accepted strategies for prophylaxis or treatment. Recent evidence suggests that anesthetics\nmight cause persistent deficits in synaptogenesis by disrupting key events in neurodevelopment.\nUsing an in vitro model consisting of dissociated primary cultured mouse neurons, we demonstrate\nabnormal pre- and post-synaptic marker expression after a clinically-relevant isoflurane anesthesia\nexposure is conducted during neuron development. We find that pharmacologic inhibition\nof the mechanistic target of rapamycin (mTOR) pathway can reverse the observed changes.\nIsoflurane exposure increases expression of phospho-S6, a marker of mTOR pathway activity,\nin a concentration-dependent fashion and this effect occurs throughout neuronal development.\nThe mTOR 1 complex (mTORC1) and the mTOR 2 complex (mTORC2) branches of the pathway\nare both activated by isoflurane exposure and this is reversible with branch-specific inhibitors.\nUpregulation of mTOR is also seen with sevoflurane and propofol exposure, suggesting that this\nmechanism of developmental anesthetic neurotoxicity may occur with all the commonly used GAs in\npediatric practice. We conclude that GAs disrupt the development of neurons during development\nby activating a well-defined neurodevelopmental disease pathway and that this phenotype can be\nreversed by pharmacologic inhibition.
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