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Infantile spasms in down syndrome: Rescue by knockdown of the GIRK2 channel
Author(s) -
Joshi Krutika,
Shen Lily,
Michaeli Avner,
Salter Michael,
ThibaultMessier Gabrielle,
Hashmi Sumaiya,
Eubanks James H.,
Cortez Miguel A.,
Snead O. Carter
Publication year - 2016
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24749
Subject(s) - gabab receptor , agonist , gene knockdown , g protein coupled inwardly rectifying potassium channel , potassium channel , baclofen , chemistry , mutant , neuroscience , microbiology and biotechnology , biology , receptor , biophysics , biochemistry , g protein , gene
Objective The Ts65Dn (Ts) mouse model of Down syndrome (DS) is exquisitely sensitive to an infantile spasms phenotype induced by γ‐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. Ann Neurol 2016;80:511–521