The GIRK 2 subunit is involved in IS‐like seizures induced by GABA B receptor agonists

Summary 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 ( GIRK 2) gene, KCNJ 6 , is overexpressed in Ts mice, and the GABA B R‐mediated GIRK 2 current is significantly increased in these mutant animals as well. Therefore, we formulated the hypothesis that the GIRK 2 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 GIRK 2 −/− , +/− , 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 ( EDE s), and quantified acute epileptic extensor spasms. Results Analysis of EEG and behavior of GIRK 2 −/− , +/− , and +/+ mice after treatment with GABA B R agonists and antagonists, indicate that GIRK 2 −/− mice are highly resistant to GABA B R agonist–induced EEG and behavioral changes. Significance These data increase the possibility that GIRK 2 channel function plays a major role in the genesis of infantile spasms.