Newly Published
Perioperative Medicine  |   August 2018
Anesthetics Have Different Effects on the Electrocorticographic Spectra of Wild-type and Mitochondrial Mutant Mice
Author Notes
  • From the Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington (C.W.C., S.C., F.K., M.M.S., P.G.M.); the Department of Anesthesiology and Pain Medicine (C.W.C., M.M.S., P.G.M.), the Division of Medical Genetics, Department of Medicine (S.C.), and the Department of Neurological Surgery (F.K.), University of Washington, Seattle, Washington.
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Presented in part to the American Society of Anesthesiologists in Boston, Massachusetts, October 22, 2017. C.W.C. and S.C. are first authors and contributed equally to each other.
    Presented in part to the American Society of Anesthesiologists in Boston, Massachusetts, October 22, 2017. C.W.C. and S.C. are first authors and contributed equally to each other.×
  • The remaining three authors, F.K., M.M.S., and P.G.M., are senior authors and contributed equally to each other but not to C.W.C. and S.C.
    The remaining three authors, F.K., M.M.S., and P.G.M., are senior authors and contributed equally to each other but not to C.W.C. and S.C.×
  • Submitted for publication October 16, 2017. Accepted for publication June 13, 2018.
    Submitted for publication October 16, 2017. Accepted for publication June 13, 2018.×
  • Acknowledgments: The authors thank Beatrice Predoi, M.D., Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, for assistance with mouse care and genotyping.
    Acknowledgments: The authors thank Beatrice Predoi, M.D., Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, Washington, for assistance with mouse care and genotyping.×
  • Research Support: Supported by the Department of Anesthesiology and Pain Medicine Bonica Scholar Program, University of Washington (Seattle, Washington; to Dr. Carspecken); the Northwest Mitochondrial Research Guild (Seattle, Washington; to Dr. Chanprasert); National Institutes of Health (Baltimore, Maryland) grant No. R01GM105696 and the Northwest Mitochondrial Research Guild (to Drs. Sedensky and Morgan); and National Institutes of Health/National Institute of Neurological Disorders and Stroke (Bethesda, Maryland) grant No. R01NS102796, the Citizens United for Research in Epilepsy (Chicago, Illinois) Epilepsy Research Grant, and Ellenbogen Chair, University of Washington Neurosurgery Research Funds (to Dr. Kalume).
    Research Support: Supported by the Department of Anesthesiology and Pain Medicine Bonica Scholar Program, University of Washington (Seattle, Washington; to Dr. Carspecken); the Northwest Mitochondrial Research Guild (Seattle, Washington; to Dr. Chanprasert); National Institutes of Health (Baltimore, Maryland) grant No. R01GM105696 and the Northwest Mitochondrial Research Guild (to Drs. Sedensky and Morgan); and National Institutes of Health/National Institute of Neurological Disorders and Stroke (Bethesda, Maryland) grant No. R01NS102796, the Citizens United for Research in Epilepsy (Chicago, Illinois) Epilepsy Research Grant, and Ellenbogen Chair, University of Washington Neurosurgery Research Funds (to Dr. Kalume).×
  • Competing Interests: The authors declare no competing interests.
    Competing Interests: The authors declare no competing interests.×
  • Correspondence: Address correspondence to Dr. Morgan: Room 923, Center for Integrative Brain Research, Seattle Children’s Research Institute, 1900 9th Ave., Seattle, Washington 98195. philip.morgan@seattlechildrens.org. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Central and Peripheral Nervous Systems
Perioperative Medicine   |   August 2018
Anesthetics Have Different Effects on the Electrocorticographic Spectra of Wild-type and Mitochondrial Mutant Mice
Anesthesiology Newly Published on August 2, 2018. doi:10.1097/ALN.0000000000002368
Anesthesiology Newly Published on August 2, 2018. doi:10.1097/ALN.0000000000002368
Abstract

What We Already Know about This Topic:

  • In genetically engineered mice that lack a specific protein (Ndufs4) in complex I of the electron transport chain in mitochondria of glutamatergic neurons, sensitivity to volatile anesthetics is markedly increased; by contrast, these mice are resistant to the anesthetic action of ketamine

  • Whether the differing sensitivity to volatile anesthetics and to ketamine in the Ndufs4 knockout mice is reflected in cortical electrical activity, measured by electrocorticography, was determined

What This Article Tells Us That Is New:

  • While isoflurane and halothane suppressed electrocor ticography in all frequency bands in control mice, in Ndufs4 knockout mice, both agents decreased power in the higher frequency bands (beta, gamma), whereas activity in the lower bands (delta, theta, and alpha) was maintained

  • Ketamine also decreased power in the Ndufs4 knockout mice in the beta and gamma frequency bands only

  • The data indicate that in Ndufs4 knockout mice, an energetic state in glutamatergic neurons impacts anesthetic sensitivity, and this sensitivity is reflected in cortical electrical activity

Background: Knockout of the mitochondrial protein Ndufs4 (Ndufs4[KO]) in mice causes hypersensitivity to volatile anesthetics but resistance to ketamine. The authors hypothesized that electrocorticographic changes underlying the responses of Ndufs4(KO) to volatile anesthetics and to ketamine would be similar in mutant and control mice.

Methods: Electrocorticographic recordings at equipotent volatile anesthetic concentrations were compared between genotypes. In separate studies, control and cell type-specific Ndufs4(KO) mice were anesthetized with intraperitoneal ketamine to determine their ED50s.

Results: Ndufs4 (KO) did not differ from controls in baseline electrocorticography (N = 5). Compared to baseline, controls exposed to isoflurane (EC50) lost power (expressed as mean baseline [µV2/Hz]; mean isoflurane [µV2/Hz]) in delta (2.45; 0.50), theta (1.41; 0.16), alpha (0.23; 0.05), beta (0.066; 0.016), and gamma (0.020; 0.005) frequency bands (N = 5). Compared to baseline, at their isoflurane EC50, Ndufs4(KO) maintained power in delta (1.08; 1.38), theta (0.36; 0.26), and alpha (0.09; 0.069) frequency bands but decreased in beta (0.041; 0.023) and gamma (0.020; 0.0068) frequency bands (N = 5). Similar results were seen for both genotypes in halothane. Vesicular glutamate transporter 2 (VGLUT2)-specific Ndufs4(KO) mice were markedly resistant to ketamine (ED50; 125 mg/kg) compared to control mice (ED50; 75 mg/kg; N = 6). At their respective ED95s for ketamine, mutant (N = 5) electrocorticography spectra showed a decrease in power in the beta (0.040; 0.020) and gamma (0.035; 0.015) frequency bands not seen in controls (N = 7).

Conclusions: Significant differences exist between the electrocorticographies of mutant and control mice at equipotent doses for volatile anesthetics and ketamine. The energetic state specifically of excitatory neurons determines the behavioral response to ketamine.