Sensitivity to isoflurane anesthesia increases in autism spectrum disorder Shank3+/∆c mutant mouse model

Changsheng Li; Michele Schaefer; Christy Gray; Ya Yang; Orion Furmanski; Sufang Liu; Paul Worley; C David Mintz; Feng Tao; Roger A Johns

doi:10.1016/j.ntt.2016.11.002

Sensitivity to isoflurane anesthesia increases in autism spectrum disorder Shank3^+/∆c mutant mouse model

Neurotoxicol Teratol. 2017 Mar-Apr:60:69-74. doi: 10.1016/j.ntt.2016.11.002. Epub 2016 Nov 14.

Authors

Affiliations

¹ Department of Anesthesiology, Affiliated Anti-cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province 450008, China; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Basic Medical School of Zhengzhou University, Zhengzhou, Henan Province 450001, China.
⁴ Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁵ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Anesthesiology and Critical Care Medicine, Department of Biomedical Sciences, Texas A&M University Baylor College of Dentistry, Dallas, TX 75246, USA.
⁶ Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: rajohns@jhmi.edu.

Abstract

Autism is a heterogeneous developmental disorder characterized by impaired social interaction, impaired communication skills, and restricted and repetitive behavior. The abnormal behaviors of these patients can make their anesthetic and perioperative management difficult. Evidence in the literature suggests that some patients with autism or specific autism spectrum disorders (ASD) exhibit altered responses to pain and to anesthesia or sedation. A genetic mouse model of one particular ASD, Phelan McDermid Syndrome, has been developed that has a Shank3 haplotype truncation (Shank3^+/Δc). These mice exhibit important characteristics of autism that mimic human autistic behavior. Our study demonstrates that a Shank3^+/ΔC mutation in mice is associated with a reduction in both the MAC and RREC50 of isoflurane and down regulation of NR1 in vestibular nuclei and PSD95 in spinal cord. Decreased expression of NR1 and PSD95 in the central nervous system of Shank3^+/ΔC mice could help reduce the MAC and RREC50 of isoflurane, which would warrant confirmation in a clinical study. If Shank3 mutations are found to affect anesthetic sensitivity in patients with ASD, better communication and stricter monitoring of anesthetic depth may be necessary.

Keywords: Autism Spectrum Disorder; Isoflurane; NR1; PSD95; Shank3.

MeSH terms

Animals
Autism Spectrum Disorder / genetics
Autism Spectrum Disorder / metabolism
Disks Large Homolog 4 Protein / biosynthesis
Dose-Response Relationship, Drug
Isoflurane / pharmacology*
Male
Mice
Microfilament Proteins
Mutation
Nerve Tissue Proteins / biosynthesis
Nerve Tissue Proteins / genetics*
Receptors, N-Methyl-D-Aspartate / biosynthesis
Reflex, Righting / drug effects
Rotarod Performance Test
Spinal Cord / metabolism
Vestibular Nuclei / metabolism

Substances

Disks Large Homolog 4 Protein
Dlg4 protein, mouse
Gprin1 protein, mouse
Microfilament Proteins
Nerve Tissue Proteins
Receptors, N-Methyl-D-Aspartate
Shank3 protein, mouse
Isoflurane

Abstract

MeSH terms

Substances

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