title: Anesthetics interfere with the polarization of developing cortical neurons.
abstract: Numerous studies from the clinical and preclinical literature indicate that general anesthetic agents have toxic effects on the developing brain, but the mechanism of this toxicity is still unknown. Previous studies have focused on the effects of anesthetics on cell survival, dendrite elaboration, and synapse formation, but little attention has been paid to possible effects of anesthetics on the developing axon. Using dissociated mouse cortical neurons in culture, we found that isoflurane delays the acquisition of neuronal polarity by interfering with axon specification. The magnitude of this effect is dependent on isoflurane concentration and exposure time over clinically relevant ranges, and it is neither a precursor to nor the result of neuronal cell death. Propofol also seems to interfere with the acquisition of neuronal polarity, but the mechanism does not require activity at GABAA receptors. Rather, the delay in axon specification likely results from a slowing of the extension of prepolarized neurites. The effect is not unique to isoflurane as propofol also seems to interfere with the acquisition of neuronal polarity. These findings demonstrate that anesthetics may interfere with brain development through effects on axon growth and specification, thus introducing a new potential target in the search for mechanisms of pediatric anesthetic neurotoxicity.
authors.affiliation: Department of Anesthesiology, Columbia University, New York, NY 10032, USA. cdm2134@columbia.edu
authors.forename: Cyrus David
authors.initials: CD
authors.lastname: Mintz
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Smith
authors.forename: Kendall M S
authors.initials: KM
authors.lastname: Barrett
authors.forename: Deanna L
authors.initials: DL
authors.lastname: Benson
mesh_terms: D000777:Anesthetics / Q000633:toxicity*; D018686:Anesthetics, Intravenous / Q000633:toxicity; D000818:Animals; D001369:Axons / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects*; D005260:Female; D007150:Immunohistochemistry; D007530:Isoflurane / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000187:drug effects*; D011247:Pregnancy; D015742:Propofol / Q000633:toxicity
chemical_list: D000777:Anesthetics; D018686:Anesthetics, Intravenous; D007530:Isoflurane; D015742:Propofol