Infantile spasms in down syndrome: Rescue by knockdown of the GIRK2 channel

Objective: The Ts65Dn (Ts) mouse model of Down syndrome (DS) is exquisitely sensitive to an infantile spasms phenotype induced by gamma-aminobutyric acid(B) receptor (GABA(B)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 GABA(B)R-coupled G protein-coupled inward rectifying potassium channel subunit 2 (GIRK2) channel. We test the hypothesis that GIRK2 is necessary for the GABA(B)R agonist-induced infantile spasms phenotype in Ts. Methods: We assessed the result of either genetic or pharmacological knockdown of the GIRK2 channel in Ts brain upon the GABA(B)R agonist-induced infantile spasms phenotype in the Ts mouse model of DS. As well, we examined GABA(B)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. Results: The reduction of the copy number of Kcnj6 in Ts mice rescued the GABA(B)R agonist-induced infantile spasms phenotype. There was an increase in GABA(B)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 GABA(B)R agonist-induced infantile spasms phenotype in Ts mutants. Interpretation: The GABA(B)R-coupled GIRK2 channel is necessary for the GABA(B)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.