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

• Published in: Annals of neurology 2016-10, Vol.80 (4), p.511-521
• Main Authors: Joshi, Krutika, Shen, Lily, Michaeli, Avner, Salter, Michael, Thibault-Messier, Gabrielle, Hashmi, Sumaiya, Eubanks, James H., Cortez, Miguel A., Snead, O. Carter
• Format: Article
• Language: English
• Subjects: Animals; Bee Venoms - pharmacology; Convulsions & seizures; Disease Models, Animal; Down Syndrome; Female; G Protein-Coupled Inwardly-Rectifying Potassium Channels - antagonists & inhibitors; G Protein-Coupled Inwardly-Rectifying Potassium Channels - drug effects; G Protein-Coupled Inwardly-Rectifying Potassium Channels - genetics; G Protein-Coupled Inwardly-Rectifying Potassium Channels - metabolism; GABA-B Receptor Agonists - pharmacology; Genotype & phenotype; Hippocampus - metabolism; Hippocampus - physiopathology; Humans; Infant, Newborn; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons - metabolism; Neurons - physiology; Phenotype; Potassium Channel Blockers - pharmacology; Receptors, GABA-B - metabolism; Spasms, Infantile - chemically induced; Spasms, Infantile - genetics; Spasms, Infantile - metabolism; Synaptic Potentials - physiology; Trisomy
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.24749

Objective The Ts65Dn (Ts) mouse model of Down syndrome (DS) is exquisitely sensitive to an infantile spasms phenotype induced by γ‐aminobutyric acidB receptor (GABABR) 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 GABABR‐coupled G protein‐coupled inward rectifying potassium channel subunit 2 (GIRK2) channel. We test the hypothesis that GIRK2 is necessary for the GABABR 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 GABABR agonist‐induced infantile spasms phenotype in the Ts mouse model of DS. As well, we examined GABABR 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 GABABR agonist‐induced infantile spasms phenotype. There was an increase in GABABR‐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 GABABR agonist‐induced infantile spasms phenotype in Ts mutants. Interpretation The GABABR‐coupled GIRK2 channel is necessary for the GABABR 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