title: Infantile spasms in down syndrome: Rescue by knockdown of the GIRK2 channel.
abstract: The Ts65Dn (Ts) mouse model of Down syndrome (DS) is exquisitely sensitive to an infantile spasms phenotype induced by γ-aminobutyric acidB receptor (GABAB R) agonists. The Ts mouse contains the core genomic triplication of the DS critical region, which includes 3 copies of the Kcnj6 gene that encodes the GABAB R-coupled G protein-coupled inward rectifying potassium channel subunit 2 (GIRK2) channel. We test the hypothesis that GIRK2 is necessary for the GABAB R agonist-induced infantile spasms phenotype in Ts.
  
  
  
  We assessed the result of either genetic or pharmacological knockdown of the GIRK2 channel in Ts brain upon the GABAB R agonist-induced infantile spasms phenotype in the Ts mouse model of DS. As well, we examined GABAB R currents in hippocampal neurons prepared from GIRK2-trisomic Ts control mice and GIRK2-disomic Ts mice in which Kcnj6 had been genetically knocked down from 3 to 2 copies.
  
  
  
  The reduction of the copy number of Kcnj6 in Ts mice rescued the GABAB R agonist-induced infantile spasms phenotype. There was an increase in GABAB R-mediated GIRK2 currents in GIRK2-trisomic Ts mouse hippocampal neurons, which were normalized in the GIRK2-disomic Ts mice. Similarly, pharmacological knockdown of the GIRK2 channel in Ts brain using the GIRK antagonist tertiapin-Q also rescued the GABAB R agonist-induced infantile spasms phenotype in Ts mutants.
  
  
  
  The GABAB R-coupled GIRK2 channel is necessary for the GABAB R agonist-induced infantile spasms phenotype in the Ts mouse and may represent a novel therapeutic target for the treatment of infantile spasms in DS. Ann Neurol 2016;80:511-521.
authors.affiliation: Neuroscience and Mental Health Program, Hospital for Sick Children, Toronto, Ontario, Canada. krutika.joshi@mail.utoronto.ca.|Department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. krutika.joshi@mail.utoronto.ca.
authors.forename: Krutika
authors.initials: K
authors.lastname: Joshi
authors.affiliation: Neuroscience and Mental Health Program, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Lily
authors.initials: L
authors.lastname: Shen
authors.affiliation: Neuroscience and Mental Health Program, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Avner
authors.initials: A
authors.lastname: Michaeli
authors.affiliation: Neuroscience and Mental Health Program, Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.|Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Salter
authors.affiliation: Neuroscience and Mental Health Program, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Thibault-Messier
authors.affiliation: Neuroscience and Mental Health Program, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Sumaiya
authors.initials: S
authors.lastname: Hashmi
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.|Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.|University Health Network, Toronto Western Research Institute, Toronto, Ontario, Canada.
authors.forename: James H
authors.initials: JH
authors.lastname: Eubanks
authors.affiliation: Neuroscience and Mental Health Program, Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Cortez
authors.affiliation: Neuroscience and Mental Health Program, Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.|Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.|Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: O Carter
authors.initials: OC
authors.lastname: Snead
mesh_terms: D000818:Animals; D001514:Bee Venoms / Q000494:pharmacology; D004195:Disease Models, Animal; D004314:Down Syndrome; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D058786:GABA-B Receptor Agonists / Q000494:pharmacology*; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D010641:Phenotype; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D018080:Receptors, GABA-B / Q000378:metabolism*; D013036:Spasms, Infantile / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D055366:Synaptic Potentials / Q000502:physiology; D014314:Trisomy
chemical_list: D001514:Bee Venoms; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D058786:GABA-B Receptor Agonists; C497069:Kcnj6 protein, mouse; D026902:Potassium Channel Blockers; D018080:Receptors, GABA-B; C029738:tertiapin