4.2 Article

Kcnj6(GIRK2) trisomy is not sufficient for conferring the susceptibility to infantile spasms seen in the Ts65Dn mouse model of down syndrome

Journal

EPILEPSY RESEARCH
Volume 145, Issue -, Pages 82-88

Publisher

ELSEVIER SCIENCE BV
DOI: 10.1016/j.eplepsyres.2018.06.006

Keywords

Electrodecremental response (EDR); Extension spasms; Electroencephalography (EEG)

Funding

  1. Canadian Institutes of Health Research [232232]

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Objective: Infantile spasms (IS) is a catastrophic childhood seizure disorder that is characterized by extensor and/or flexor spasms, cognitive deterioration and a characteristic EEG abnormality. The latter consists of a pattern of a spike-wave followed by an electrodecremental response (EDR), which is a flattening of the EEG waveform amplitude. The mechanism/circuitry that underpins IS is unknown. Children with Down Syndrome (DS) are particularly vulnerable to IS. The standard mouse model of DS is the Ts65Dn mutant mouse (Ts). Using the Ts mouse, we have created an animal model of IS in DS. This model entails the treatment of Ts mice with a GABA(B)R agonist with a resultant recapitulation of the semiological, electrographic, and pharmacological phenotype of IS. One of the genes triplicated in Ts mice is the kcnj6 gene which codes for the G-protein inwardly rectifying potassium channel 2 (GIRK2) protein. We have shown that over expression of GIRK2 in Ts brain is necessary for the production of the GABA(B)R agonist induced IS phenotype in the Ts mouse. Here, we ask the question whether the excess GIRK2 is sufficient for the production of the GABA(B)R agonist induced IS phenotype. Methods: To address this question, we used kcnj6 triploid mice, and compared the number of spasms via video analysis and EDR events via EEG to that of the WT mice. Results: We now show that GABA(B)R agonist-treated kcnj6 triploid mice failed to show susceptibility to the IS phenotype. Therefore, over expression of GIRK2 in the brain is necessary, but not sufficient to confer susceptibility to the GABA(B)R agonist-induced IS phenotype in the Ts model of DS. Significance: It is therefore likely that GIRK2 is working in concert with another factor or factors that are altered in the Ts brain in the production of the GABA(B)R agonist-induced IS phenotype.

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