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

Martin Pushkarjov, Hubert Fiumelli, Adrian Briner, Timea Bodogan, Kornel Demeter, Claudia-Marvine Lacoh, Martina Mavrovic, Peter Blaesse, Kai Kalervo Kaila, Laszlo Vutskits

Research output: Contribution to journalArticleScientificpeer-review

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.
Original languageEnglish
JournalAnesthesiology
Volume126
Issue number5
Pages (from-to)855-867
Number of pages13
ISSN0003-3022
DOIs
Publication statusPublished - 2017
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 3126 Surgery, anesthesiology, intensive care, radiology

Cite this

Pushkarjov, Martin ; Fiumelli, Hubert ; Briner, Adrian ; Bodogan, Timea ; Demeter, Kornel ; Lacoh, Claudia-Marvine ; Mavrovic, Martina ; Blaesse, Peter ; Kaila, Kai Kalervo ; Vutskits, Laszlo. / K-Cl Cotransporter 2–mediated Cl− Extrusion Determines Developmental Stage–dependent Impact of Propofol Anesthesia on Dendritic Spines. In: Anesthesiology. 2017 ; Vol. 126, No. 5. pp. 855-867.
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title = "K-Cl Cotransporter 2–mediated Cl− Extrusion Determines Developmental Stage–dependent Impact of Propofol Anesthesia on Dendritic Spines",
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.",
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author = "Martin Pushkarjov and Hubert Fiumelli and Adrian Briner and Timea Bodogan and Kornel Demeter and Claudia-Marvine Lacoh and Martina Mavrovic and Peter Blaesse and Kaila, {Kai Kalervo} and Laszlo Vutskits",
year = "2017",
doi = "10.1097/ALN.0000000000001587",
language = "English",
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pages = "855--867",
journal = "Anesthesiology",
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K-Cl Cotransporter 2–mediated Cl− Extrusion Determines Developmental Stage–dependent Impact of Propofol Anesthesia on Dendritic Spines. / Pushkarjov, Martin; Fiumelli, Hubert ; Briner, Adrian; Bodogan, Timea; Demeter, Kornel; Lacoh, Claudia-Marvine; Mavrovic, Martina; Blaesse, Peter; Kaila, Kai Kalervo; Vutskits, Laszlo.

In: Anesthesiology, Vol. 126, No. 5, 2017, p. 855-867.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - K-Cl Cotransporter 2–mediated Cl− Extrusion Determines Developmental Stage–dependent Impact of Propofol Anesthesia on Dendritic Spines

AU - Pushkarjov, Martin

AU - Fiumelli, Hubert

AU - Briner, Adrian

AU - Bodogan, Timea

AU - Demeter, Kornel

AU - Lacoh, Claudia-Marvine

AU - Mavrovic, Martina

AU - Blaesse, Peter

AU - Kaila, Kai Kalervo

AU - Vutskits, Laszlo

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - 3126 Surgery, anesthesiology, intensive care, radiology

U2 - 10.1097/ALN.0000000000001587

DO - 10.1097/ALN.0000000000001587

M3 - Article

VL - 126

SP - 855

EP - 867

JO - Anesthesiology

JF - Anesthesiology

SN - 0003-3022

IS - 5

ER -