Monica Blichowski is a second year medical student at the University of Toronto.
SUMMARYObjective: 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 c-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 Rmediated 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: GIRK2À/À , +/À , and +/+ mice were treated with c-butyrolactone (GBL), a prodrug of the GABA B R agonist c-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 À/À , +/À , and +/+ mice after treatment with GABA B R agonists and antagonists, indicate that GIRK2 À/À mice are highly resistant to GABA B R agonist-induced EEG and behavioral changes. Significance: These data increase the possibility that GIRK2 channel function plays a major role in the genesis of infantile spasms.
