Newly Published
Perioperative Medicine  |   July 2020
Neonatal Isoflurane Anesthesia or Disruption of Postsynaptic Density-95 Protein Interactions Change Dendritic Spine Densities and Cognitive Function in Juvenile Mice
Author Notes
  • From the Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
  • Portions of this work were previously presented at the Association of University Anesthesiologists annual meeting, April 26, 2018, Chicago, Illinois, the International Anesthesia Research Society Annual Meeting, April 29, 2018, Chicago, Illinois, and the Society for Neuroscience Annual Meeting, November 3, 2018, San Diego, California.
    Portions of this work were previously presented at the Association of University Anesthesiologists annual meeting, April 26, 2018, Chicago, Illinois, the International Anesthesia Research Society Annual Meeting, April 29, 2018, Chicago, Illinois, and the Society for Neuroscience Annual Meeting, November 3, 2018, San Diego, California.×
  • Submitted for publication November 18, 2019. Accepted for publication July 1, 2020.
    Submitted for publication November 18, 2019. Accepted for publication July 1, 2020.×
  • Correspondence: Address correspondence to Dr. Johns: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 720 Rutland Ave., Ross 361, Baltimore, Maryland 21205. rajohns@jhmi.edu. Anesthesiology’s articles are made freely accessible to all readers on www.anesthesiology.org, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Central and Peripheral Nervous Systems / Pediatric Anesthesia / Pharmacology
Perioperative Medicine   |   July 2020
Neonatal Isoflurane Anesthesia or Disruption of Postsynaptic Density-95 Protein Interactions Change Dendritic Spine Densities and Cognitive Function in Juvenile Mice
Anesthesiology Newly Published on July 28, 2020. doi:https://doi.org/10.1097/ALN.0000000000003482
Anesthesiology Newly Published on July 28, 2020. doi:https://doi.org/10.1097/ALN.0000000000003482
Abstract

Background: Experimental evidence shows postnatal exposure to anesthesia negatively affects brain development. The PDZ2 domain, mediating protein–protein interactions of the postsynaptic density-95 protein, serves as a molecular target for several inhaled anesthetics. The authors hypothesized that early postnatal disruption of postsynaptic density-95 PDZ2 domain interactions has persistent effects on dendritic spines and cognitive function.

Methods: One-week-old mice were exposed to 1.5% isoflurane for 4 h or injected with 8 mg/kg active postsynaptic density-95 wild-type PDZ2 peptide along with their respective controls. A subset of these mice also received 4 mg/kg of the nitric oxide donor molsidomine. Hippocampal spine density, long-term potentiation, novel object recognition memory, and fear learning and memory were evaluated in mice.

Results: Exposure of 7-day-old mice to isoflurane or postsynaptic density-95 wild-type PDZ2 peptide relative to controls causes: (1) a long-term decrease in mushroom spines at 7 weeks (mean ± SD [spines per micrometer]): control (0.8 ± 0.2) versus isoflurane (0.4 ± 0.2), P < 0.0001, and PDZ2MUT (0.7 ± 0.2) versus PDZ2WT (0.4 ± 0.2), P < 0.001; (2) deficits in object recognition at 6 weeks (mean ± SD [recognition index]): naïve (70 ± 8) versus isoflurane (55 ± 14), P = 0.010, and control (65 ± 13) versus isoflurane (55 ± 14), P = 0.045, and PDZ2MUT (64 ±11) versus PDZ2WT (53 ± 18), P = 0.045; and (3) deficits in fear learning at 7 weeks and memory at 8 weeks (mean ± SD [% freezing duration]): Learning, control (69 ± 12) versus isoflurane (52 ± 13), P < 0.0001, and PDZ2MUT (65 ± 14) versus PDZ2WT (55 ± 14) P = 0.011, and Memory, control (80 ± 17) versus isoflurane (56 ± 23), P < 0.0001 and PDZ2MUT (73 ± 18) versus PDZ2WT (44 ± 19) P < 0.0001. Impairment in long-term potentiation has fully recovered here at 7 weeks (mean ± SD [% baseline]): control (140 ± 3) versus isoflurane (137 ± 8), P = 0.560, and PDZ2MUT (136 ± 17) versus PDZ2WT (128 ± 11), P = 0.512. The isoflurane induced decrease in mushroom spines was preventable by introduction of a nitric oxide donor.

Conclusions: Early disruption of PDZ2 domain-mediated protein–protein interactions mimics isoflurane in decreasing mushroom spine density and causing learning and memory deficits in mice. Prevention of the decrease in mushroom spine density with a nitric oxide donor supports a role for neuronal nitric oxide synthase pathway in mediating this cellular change associated with cognitive impairment.

Editor’s Perspective:

What We Already Know about This Topic:

  • PDZ2 domains of postsynaptic density-95 proteins bind to the NR2 subunit of the N-methyl-d-aspartate (NMDA) receptor and promote synaptogenesis

  • PDZ2 domains are molecular targets for inhalational anesthetics

What This Article Tells Us That Is New:

  • Disruption of PDZ2 domain-mediated protein–protein interactions or a 4-h-long isoflurane anesthesia in 7-day-old mice induced comparable lasting deficits in synaptogenesis and cognitive function, and these effects were prevented by administration of the nitric oxide donor molsidomine

  • These experimental observations suggest the involvement of a pathway involving the NMDA receptor, postsynaptic density protein-95, and nitric oxide signaling in isoflurane exposure-induced cognitive impairment in mice