Cell age–specific vulnerability of neurons to anesthetic toxicity

Authors

  • Rylon D. Hofacer BS,

    1. Department of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
    2. Program in Neuroscience, University of Cincinnati, Cincinnati, OH
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  • Meng Deng MD,

    1. Department of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
    2. Department of Anesthesiology, Children's Hospital of Fudan University, Shanghai, China
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  • Christopher G. Ward MD,

    1. Department of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
    2. Departments of Anesthesiology and Pediatrics, University of Cincinnati, Cincinnati, OH
    Current affiliation:
    1. Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia, Philadelphia, PA
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  • Bernadin Joseph BS,

    1. Department of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
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  • Elizabeth A. Hughes BS,

    1. Department of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
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  • Connie Jiang,

    1. Department of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
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  • Steve C. Danzer PhD,

    1. Department of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
    2. Program in Neuroscience, University of Cincinnati, Cincinnati, OH
    3. Departments of Anesthesiology and Pediatrics, University of Cincinnati, Cincinnati, OH
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  • Andreas W. Loepke MD, PhD

    Corresponding author
    1. Program in Neuroscience, University of Cincinnati, Cincinnati, OH
    2. Departments of Anesthesiology and Pediatrics, University of Cincinnati, Cincinnati, OH
    • Department of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
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Address correspondence to Dr Loepke, Cincinnati Children's Hospital Medical Center, Department of Anesthesiology, 3333 Burnet Ave, Cincinnati, OH 45229. E-mail: pedsanesthesia@gmail.com

Abstract

Objective

Anesthetics have been linked to widespread neuronal cell death in neonatal animals. Epidemiological human studies have associated early childhood anesthesia with long-term neurobehavioral abnormalities, raising substantial concerns that anesthetics may cause similar cell death in young children. However, key aspects of the phenomenon remain unclear, such as why certain neurons die, whereas immediately adjacent neurons are seemingly unaffected, and why the immature brain is exquisitely vulnerable, whereas the mature brain seems resistant. Elucidating these questions is critical for assessing the phenomenon's applicability to humans, defining the susceptible age, predicting vulnerable neuronal populations, and devising mitigating strategies.

Methods

This study examines the effects of anesthetic exposure on late- and adult-generated neurons in newborn, juvenile, and adult mice, and characterizes vulnerable cells using birth-dating and immunohistochemical techniques.

Results

We identify a critical period of cellular developmental during which neurons are susceptible to anesthesia-induced apoptosis. Importantly, we demonstrate that anesthetic neurotoxicity can extend into adulthood in brain regions with ongoing neurogenesis, such as dentate gyrus and olfactory bulb.

Interpretation

Our findings suggest that anesthetic vulnerability reflects the age of the neuron, not the age of the organism, and therefore may potentially not only be relevant to children but also to adults undergoing anesthesia. This observation further predicts differential heightened regional vulnerability to anesthetic neuroapoptosis to closely follow the distinct regional peaks in neurogenesis. This knowledge may help guide neurocognitive testing of specific neurological domains in humans following exposure to anesthesia, dependent on the individual's age during exposure. ANN NEUROL 2013;73:695–704

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