title: Long-term effects of single or multiple neonatal sevoflurane exposures on rat hippocampal ultrastructure.
abstract: BACKGROUND
  Neonatal exposure to general anesthetics may pose significant neurocognitive risk. Human epidemiological studies demonstrate higher rates of learning disability among children with multiple, but not single, exposures to anesthesia. The authors employ a rat model to provide a histological correlate for these population-based observations. The authors examined long-term differences in hippocampal synaptic density, mitochondrial density, and dendritic spine morphology.
  
  
  METHODS
  Twenty male rat pups (n = 5/condition) were exposed to 2.5% sevoflurane under one of four conditions: single 2-h exposure on postnatal day 7 (P7); single 6-h exposure on P7; repeated 2-h exposures on P7, P10, and P13 for a cumulative 6 h of general anesthetics; or control exposure to 30% oxygen on P7, P10, and P13.
  
  
  RESULTS
  Repeated exposure to general anesthetics resulted in greater synaptic loss relative to a single 2-h exposure (P < 0.001). The magnitude of synaptic loss induced by three 2-h exposures (1.977 ± 0.040 μm [mean ± SEM]) was more profound than that of a single 6-h exposure (2.280 ± 0.045 μm, P = 0.022). Repeated exposures did not alter the distribution of postsynaptic density length, indicating a uniform pattern of loss across spine types. In contrast, mitochondrial toxicity was best predicted by the cumulative duration of exposure. Relative to control (0.595 ± 0.017), both repeated 2-h exposures (0.479 ± 0.015) and a single 6-h exposure (0.488 ± 0.013) were associated with equivalent reductions in the fraction of presynaptic terminals containing mitochondria (P < 0.001).
  
  
  CONCLUSIONS
  This suggests a "threshold effect" for general anesthetic-induced neurotoxicity, whereby even brief exposures induce long-lasting alterations in neuronal circuitry and sensitize surviving synapses to subsequent loss.
authors.affiliation: From the Department of Anesthesiology (L.G.A.), Department of Neuroscience (M.L.S.), Departments of Neuroscience, Anesthesiology, and Geriatrics and Palliative Medicine (M.G.B.), the Icahn School of Medicine at Mount Sinai, New York, New York; and the Department of Biomedical Services, University of Oxford, Oxford, United Kingdom (K.L.M.).
authors.forename: Levana G
authors.initials: LG
authors.lastname: Amrock
authors.forename: Mathew L
authors.initials: ML
authors.lastname: Starner
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Murphy
authors.forename: Mark G
authors.initials: MG
authors.lastname: Baxter
mesh_terms: D000768:Anesthesia, General / Q000009:adverse effects / Q000379:methods; D018681:Anesthetics, General / Q000633:toxicity; D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology / Q000648:ultrastructure*; D006801:Humans; D008297:Male; D008738:Methyl Ethers / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D000077149:Sevoflurane; D013569:Synapses / Q000187:drug effects; D013995:Time
chemical_list: D018681:Anesthetics, General; D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D000077149:Sevoflurane