Infantile spasms in down syndrome: Rescue by knockdown of the GIRK2 channel.
Ann Neurol
; 80(4): 511-21, 2016 10.
Article
em En
| MEDLINE
| ID: mdl-27462820
ABSTRACT
OBJECTIVE:
The Ts65Dn (Ts) mouse model of Down syndrome (DS) is exquisitely sensitive to an infantile spasms phenotype induced by γ-aminobutyric acidB receptor (GABAB 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 GABAB R-coupled G protein-coupled inward rectifying potassium channel subunit 2 (GIRK2) channel. We test the hypothesis that GIRK2 is necessary for the GABAB 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 GABAB R agonist-induced infantile spasms phenotype in the Ts mouse model of DS. As well, we examined GABAB 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 GABAB R agonist-induced infantile spasms phenotype. There was an increase in GABAB 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 GABAB R agonist-induced infantile spasms phenotype in Ts mutants.INTERPRETATION:
The GABAB R-coupled GIRK2 channel is necessary for the GABAB 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;80511-521.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Espasmos Infantis
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Receptores de GABA-B
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Bloqueadores dos Canais de Potássio
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Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G
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Agonistas dos Receptores de GABA-B
Limite:
Animals
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Female
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Humans
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Male
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Newborn
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article