title: The GIRK2 subunit is involved in IS-like seizures induced by GABA(B) receptor agonists.
abstract: OBJECTIVE
  Infantile spasms (or IS) is a catastrophic childhood epilepsy that is particularly prevalent in children with Down syndrome. Previously, we have shown that the Ts65Dn (Ts) mouse model of Down syndrome is a useful substrate upon which to develop an animal model of infantile spasms. Specifically, the Ts mouse is exquisitely sensitive to the electroencephalography (EEG) and behavioral effects of γ-aminobutyric acid (GABA) B receptor (GABA(B)R) agonists with a resultant phenotype that bears behavioral, EEG, and pharmacologic semblance to infantile spasms in humans. The G protein-coupled inward rectifying potassium channel subunit 2 (GIRK2) gene, KCNJ6, is overexpressed in Ts mice, and the GABA(B)R-mediated GIRK2 current is significantly increased in these mutant animals as well. Therefore, we formulated the hypothesis that the GIRK2 channel plays a significant role in the behavioral (measured by acute extensor spasms quantification) and EEG (measured by the electrodecremental response duration) phenotype induced in the Ts mice by GABA(B)R agonists.
  
  
  METHODS
  GIRK2(-/-), (+/-), and (+/+) mice were treated with γ-butyrolactone (GBL), a pro-drug of the GABA(B)R agonist γ-hydroxybutyric acid, and the specific GABA(B)R agonist baclofen (BAC) under continuous EEG monitoring. These drugs induce epileptiform bursts, extensor spasms, and an electrodecremental response (EDR) in Ts mice at low doses, and in wild-type mice at high doses. A dose-response curve was ascertained with two treatment groups: GBL (100, 200, and 400 mg/kg) and BAC (4, 8, 12, and 16 mg/kg). We determined the baseline, the presence and duration of electrodecremental epochs (EDEs), and quantified acute epileptic extensor spasms.
  
  
  RESULTS
  Analysis of EEG and behavior of GIRK2(-/-), (+/-), and (+/+) mice after treatment with GABA(B)R agonists and antagonists, indicate that GIRK2(-/-) mice are highly resistant to GABA(B)R agonist-induced EEG and behavioral changes.
  
  
  CONCLUSIONS
  These data increase the possibility that GIRK2 channel function plays a major role in the genesis of infantile spasms.
authors.affiliation: Division of Neurology, SickKids Hospital, Toronto, Ontario, Canada.|Neurosciences and Mental Health Program, Peter Gilgan Centre for Research and Learning, SickKids Hospital, Toronto, Ontario, Canada.|University of Toronto, Toronto, Ontario, Canada.
authors.forename: Monica
authors.initials: M
authors.lastname: Blichowski
authors.affiliation: Division of Neurology, SickKids Hospital, Toronto, Ontario, Canada.|Neurosciences and Mental Health Program, Peter Gilgan Centre for Research and Learning, SickKids Hospital, Toronto, Ontario, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Shephard
authors.affiliation: Division of Neurology, SickKids Hospital, Toronto, Ontario, Canada.|Neurosciences and Mental Health Program, Peter Gilgan Centre for Research and Learning, SickKids Hospital, Toronto, Ontario, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: Armstrong
authors.affiliation: Neurosciences and Mental Health Program, Peter Gilgan Centre for Research and Learning, SickKids Hospital, Toronto, Ontario, Canada.
authors.forename: Liqing
authors.initials: L
authors.lastname: Shen
authors.affiliation: Division of Neurology, SickKids Hospital, Toronto, Ontario, Canada.|Neurosciences and Mental Health Program, Peter Gilgan Centre for Research and Learning, SickKids Hospital, Toronto, Ontario, Canada.|University of Toronto, Toronto, Ontario, Canada.|Department of Paediatrics, SickKids Hospital, Toronto, Ontario, Canada.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Cortez
authors.affiliation: University of Toronto, Toronto, Ontario, Canada.
authors.forename: James H
authors.initials: JH
authors.lastname: Eubanks
authors.affiliation: Division of Neurology, SickKids Hospital, Toronto, Ontario, Canada.|Neurosciences and Mental Health Program, Peter Gilgan Centre for Research and Learning, SickKids Hospital, Toronto, Ontario, Canada.|University of Toronto, Toronto, Ontario, Canada.|Department of Paediatrics, SickKids Hospital, Toronto, Ontario, Canada.
authors.forename: O Carter
authors.initials: OC
authors.lastname: Snead
mesh_terms: D000818:Animals; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000096:biosynthesis*; D018755:GABA Agonists / Q000633:toxicity*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D021122:Protein Subunits / Q000096:biosynthesis*; D018080:Receptors, GABA-B; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism*; D013036:Spasms, Infantile / Q000139:chemically induced / Q000378:metabolism*
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D018755:GABA Agonists; C497069:Kcnj6 protein, mouse; D021122:Protein Subunits; D018080:Receptors, GABA-B
keywords: Down syndrome; GIRK2 channel; Infantile spasms; Knockout; Ts65Dn