Perioperative Medicine  |   May 2017
K-Cl Cotransporter 2–mediated Cl Extrusion Determines Developmental Stage–dependent Impact of Propofol Anesthesia on Dendritic Spines
Author Notes
  • From the Department of Biosciences and Neuroscience Center (HiLIFE), University of Helsinki, Helsinki, Finland (M.P., M.M., P.B., K.K.); Division of Biological and Environmental Sciences and Technology, King Abdullah University of Science and Technology, Thuwal, Kingdom of Saudi Arabia (H.F.); Department of Anesthesiology, Pharmacology and Intensive Care, University Hospital of Geneva, Geneva, Switzerland (A.B., T.B., C.-M.L., L.V.); Department of Fundamental Neurosciences, University of Geneva Medical School, Geneva, Switzerland (A.B., T.B., K.D., L.V.); and Institute of Experimental Medicine of the Hungarian Academy of Sciences, Budapest, Hungary (K.D.). Current position: Institute of Physiology I, Westfälische Wilhelms-University Münster, Münster, Germany (P.B.).
  • M.P., H.F., and A.B. contributed equally to this article.
    M.P., H.F., and A.B. contributed equally to this article.×
  • Submitted for publication August 27, 2016. Accepted for publication February 2, 2017.
    Submitted for publication August 27, 2016. Accepted for publication February 2, 2017.×
  • Address correspondence to Dr. Vutskits: Department of Anesthesiology, Pharmacology and Intensive Care, University Hospital of Geneva, 4, Rue Gabrielle-Perret-Gentil, 1211 Geneva 4, Switzerland. laszlo.vutskits@unige.ch. 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 / Basic Science / Pharmacology
Perioperative Medicine   |   May 2017
K-Cl Cotransporter 2–mediated Cl Extrusion Determines Developmental Stage–dependent Impact of Propofol Anesthesia on Dendritic Spines
Anesthesiology 5 2017, Vol.126, 855-867. doi:10.1097/ALN.0000000000001587
Anesthesiology 5 2017, Vol.126, 855-867. doi:10.1097/ALN.0000000000001587
Abstract

Background: General anesthetics potentiating γ-aminobutyric acid (GABA)–mediated signaling are known to induce a persistent decrement in excitatory synapse number in the cerebral cortex when applied during early postnatal development, while an opposite action is produced at later stages. Here, the authors test the hypothesis that the effect of general anesthetics on synaptogenesis depends upon the efficacy of GABA receptor type A (GABAA)–mediated inhibition controlled by the developmental up-regulation of the potassium-chloride (K-Cl) cotransporter 2 (KCC2).

Methods: In utero electroporation of KCC2 was used to prematurely increase the efficacy of (GABAA)–mediated inhibition in layer 2/3 pyramidal neurons in the immature rat somatosensory cortex. Parallel experiments with expression of the inward-rectifier potassium channel Kir2.1 were done to reduce intrinsic neuronal excitability. The effects of these genetic manipulations (n = 3 to 4 animals per experimental group) were evaluated using iontophoretic injection of Lucifer Yellow (n = 8 to 12 cells per animal). The total number of spines analyzed per group ranged between 907 and 3,371.

Results: The authors found a robust effect of the developmental up-regulation of KCC2–mediated Cl transport on the age-dependent action of propofol on dendritic spines. Premature expression of KCC2, unlike expression of a transport-inactive KCC2 variant, prevented a propofol-induced decrease in spine density. In line with a reduction in neuronal excitability, the above result was qualitatively replicated by overexpression of Kir2.1.

Conclusions: The KCC2–dependent developmental increase in the efficacy of GABAA–mediated inhibition is a major determinant of the age-dependent actions of propofol on dendritic spinogenesis.