Abstracts

Rationale: Children with Down Syndrome are susceptible to infantile spasms. We have established an animal model of infantile spasms using the Ts65Dn (Ts) mouse model of Down Syndrome treated with a GABA(B) receptor [GABA(B)R] agonist, known to activate the G protein-coupled inwardly-rectifying potassium subunit 2 (Girk2) channel (Cortez et al. Pediatr Res 65: 499-503, 2009). Ts mice are known to overexpress Girk2 proteins, raising the possibility that the overexpression of Girk2 in the Ts mouse may be responsible for GABA(B)R agonist-induced infantile spasms in this model. This study was designed to test the hypothesis that the GABA(B)R modulated Girk2 channel is involved in the pathogenesis of infantile spasms-like seizures in the Ts model.Methods: Groups of Girk2 -/-, Girk2 +/-, and Girk2 +/+ mice (n=8 each) were treated with -butyrolactone (GBL), a pro-drug of the GABA(B)R agonist -hydroxybutric acid (GHB), and the specific GABA(B)R agonist baclofen (BAC) under continuous electrocorticographic (ECoG) monitoring. Both of these drugs induce infantile spasms with an electrodecremental response (EDR) in Ts mice at low doses, and in wild type mice produce spike-wave and EDR responses at high doses. A dose response curve was ascertained with 2 treatment groups: GBL (100, 200, and 400mg/kg) and BAC (4, 8, 12, and 16 mg/kg). We determined the baseline, the spike-and-wave frequency, and the presence and duration of electrodecremental epochs (EDEs). Results: The threshold dose of GBL for EDR in Girk2 +/- and +/+ mice was 200 mg/kg GBL, and the duration of EDR increased with the dose. Girk2 +/+ mice had significantly longer EDR than Girk2 +/- mice in response to 400 mg/kg GBL (p<0.05, student s t-test). Girk2 -/- mice failed to exhibit EDR at any dose of GBL. The threshold dose for EDR with BAC was 8 mg/kg in Girk2 +/- and Girk2 +/+ groups. BAC induced a significantly longer duration of EDR in Girk2 +/+ vs +/- mice (p<0.05). No EDR was observed at any of the BAC doses in the Girk2-/- mice. GABA(B)R agonist-induced EDR in the Girk2+/+ and +/- mice was blocked by the specific GABA(B)R antagonist CGP35348.Conclusions: These data provide preliminary support for the hypothesis that Girk2 channels are necessary for the generation of infantile spasms in the Ts65Dn mouse model. This work was funded by the Canadian Institutes of Health Research.