Newly Published
Perioperative Medicine  |   December 2018
Nitric Oxide Donor Prevents Neonatal Isoflurane-induced Impairments in Synaptic Plasticity and Memory
Author Notes
  • From the Department Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland.
  • Submitted for publication April 16, 2018. Accepted for publication October 25, 2018.
    Submitted for publication April 16, 2018. Accepted for publication October 25, 2018.×
  • Portions of the present work have been presented previously under the title “Neonatal Disruption of PSD-95 PDZ Domain-mediated Protein–Protein Interactions Alters Dendritic Spine Morphology, Long-term Potentiation, and Causes Deficits in Learning and Memory in Mice” at the following meetings: Association of University Anesthesiologists Annual Meeting, April 26, 2018, in Chicago, Illinois; Society of Critical Care Anesthesiologists Annual Meeting, April 27, 2018, in Chicago, Illinois; and the International Anesthesia Research Society Annual Meeting, April 29, 2018, in Chicago, Illinois.
    Portions of the present work have been presented previously under the title “Neonatal Disruption of PSD-95 PDZ Domain-mediated Protein–Protein Interactions Alters Dendritic Spine Morphology, Long-term Potentiation, and Causes Deficits in Learning and Memory in Mice” at the following meetings: Association of University Anesthesiologists Annual Meeting, April 26, 2018, in Chicago, Illinois; Society of Critical Care Anesthesiologists Annual Meeting, April 27, 2018, in Chicago, Illinois; and the International Anesthesia Research Society Annual Meeting, April 29, 2018, in Chicago, Illinois.×
  • Correspondence: Address correspondence to Dr. Johns: Johns Hopkins University School of Medicine 720 Rutland Avenue, Ross 361, Baltimore, Maryland 21205. rajohns@jhmi.edu. 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 / Pharmacology
Perioperative Medicine   |   December 2018
Nitric Oxide Donor Prevents Neonatal Isoflurane-induced Impairments in Synaptic Plasticity and Memory
Anesthesiology Newly Published on December 27, 2018. doi:10.1097/ALN.0000000000002529
Anesthesiology Newly Published on December 27, 2018. doi:10.1097/ALN.0000000000002529
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • Some general anesthetics have been shown to have adverse effects on neuronal development that affect neural function and cognitive behavior.

  • Clinically relevant concentrations of inhalational anesthetics inhibit the postsynaptic density (PSD)-95, discs large homolog, and zona occludens-1 (PDZ) domain–mediated protein–protein interaction between PSD-95 or PSD-93 and N-methyl-d-aspartate receptors or neuronal NO synthase.

What This Article Tells Us That Is New:

  • Neonatal PSD-95 PDZ2WT peptide treatment mimics the effects of isoflurane (∽1 minimum alveolar concentration) by altering dendritic spine morphology, neural plasticity, and memory without inducing detectable increases in apoptosis or changes in synaptic density.

  • These results indicate that a single dose of isoflurane (∽1 minimum alveolar concentration) or PSD-95 PDZ2WT peptide alters dendritic spine architecture and functions important for cognition in the developing brain. This impairment can be prevented by administration of the NO donor molsidomine.

Background: In humans, multiple early exposures to procedures requiring anesthesia constitute a significant risk factor for development of learning disabilities and disorders of attention. In animal studies, newborns exposed to anesthetics develop long-term deficits in cognition. Previously, our laboratory showed that postsynaptic density (PSD)-95, discs large homolog, and zona occludens-1 (PDZ) domains may serve as a molecular target for inhaled anesthetics. This study investigated a role for PDZ interactions in spine development, plasticity, and memory as a potential mechanism for early anesthetic exposure-produced cognitive impairment.

Methods: Postnatal day 7 mice were exposed to 1.5% isoflurane for 4 h or injected with 8 mg/kg active PSD-95 PDZ2WT peptide. Apoptosis, hippocampal dendritic spine changes, synapse density, long-term potentiation, and cognition functions were evaluated (n = 4 to 18).

Results: Exposure of postnatal day 7 mice to isoflurane or PSD-95 PDZ2WT peptide causes a reduction in long thin spines (median, interquartile range [IQR]: wild type control [0.54, 0.52 to 0.86] vs. wild type isoflurane [0.31, 0.16 to 0.38], P = 0.034 and PDZ2MUT [0.86, 0.67 to 1.0] vs. PDZ2WT [0.55, 0.53 to 0.59], P = 0.028), impairment in long-term potentiation (median, IQR: wild type control [123, 119 to 147] and wild type isoflurane [101, 96 to 118], P = 0.049 and PDZ2MUT [125, 119 to 131] and PDZ2WT [104, 97 to 107], P = 0.029), and deficits in acute object recognition (median, IQR: wild type control [79, 72 to 88] vs. wild type isoflurane [63, 55 to 72], P = 0.044 and PDZ2MUT [81, 69 to 84] vs. PDZ2WT [67, 57 to 77], P = 0.039) at postnatal day 21 without inducing detectable differences in apoptosis or changes in synaptic density. Impairments in recognition memory and long-term potentiation were preventable by introduction of a NO donor.

Conclusions: Early disruption of PDZ domain–mediated protein–protein interactions alters spine morphology, synaptic function, and memory. These results support a role for PDZ interactions in early anesthetic exposure–produced cognitive impairment. Prevention of recognition memory and long-term potentiation deficits with a NO donor supports a role for the N-methyl-d-aspartate receptor/PSD-95/neuronal NO synthase pathway in mediating these aspects of isoflurane-induced cognitive impairment.