K-Cl Cotransporter 2-mediated Cl- Extrusion Determines Developmental Stage-dependent Impact of Propofol Anesthesia on Dendritic Spines.

Anesthesiology 2017 05;126(5):855-867

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.).

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.

Download full-text PDF

Source
http://dx.doi.org/10.1097/ALN.0000000000001587DOI Listing
May 2017
25 Reads

Publication Analysis

Top Keywords

gabaa-mediated inhibition
12
general anesthetics
8
dendritic spines
8
developmental up-regulation
8
efficacy gabaa-mediated
8
neuronal excitability
8
increase efficacy
8
propofol dendritic
8
k-cl cotransporter
8
layer 2/3
4
prematurely increase
4
expression transport-inactive
4
kcc2 expression
4
inhibition layer
4
expression kcc2
4
spines premature
4
rat somatosensory
4
somatosensory cortex
4
immature rat
4
premature expression
4

Similar Publications