title: K-Cl Cotransporter 2-mediated Cl- Extrusion Determines Developmental Stage-dependent Impact of Propofol Anesthesia on Dendritic Spines.
abstract: 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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 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.).
authors.forename: Martin
authors.initials: M
authors.lastname: Puskarjov
authors.forename: Hubert
authors.initials: H
authors.lastname: Fiumelli
authors.forename: Adrian
authors.initials: A
authors.lastname: Briner
authors.forename: Timea
authors.initials: T
authors.lastname: Bodogan
authors.forename: Kornel
authors.initials: K
authors.lastname: Demeter
authors.forename: Claudia-Marvine
authors.initials: CM
authors.lastname: Lacoh
authors.forename: Martina
authors.initials: M
authors.lastname: Mavrovic
authors.forename: Peter
authors.initials: P
authors.lastname: Blaesse
authors.forename: Kai
authors.initials: K
authors.lastname: Kaila
authors.forename: Laszlo
authors.initials: L
authors.lastname: Vutskits
mesh_terms: D000818:Animals; D049229:Dendritic Spines / Q000187:drug effects* / Q000378:metabolism*; D018274:Electroporation; D005260:Female; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D015742:Propofol / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000187:drug effects; D013003:Somatosensory Cortex / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D027981:Symporters / Q000187:drug effects* / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*; D000096922:K Cl- Cotransporters
chemical_list: D006993:Hypnotics and Sedatives; D015742:Propofol; D018079:Receptors, GABA; D027981:Symporters; D000096922:K Cl- Cotransporters