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

Joshi, Krutika; Shen, Lily; Michaeli, Avner; Salter, Michael; Thibault-Messier, Gabrielle; Hashmi, Sumaiya; Eubanks, James H.; Cortez, Miguel A.; Snead, O. Carter

doi:10.1002/ana.24749

Cited by 22 publications

(20 citation statements)

References 48 publications

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“…Another gene that has been linked to DS is Kcnj6 , which encodes potassium-voltage-gated channel subfamily J member 6. This gene has been shown to contribute to CHDs ( Lignon et al, 2008 ) and to cognitive defects, together with another gene not yet identified ( Jiang et al, 2015 ; Joshi et al, 2016 ; Cooper et al, 2012 ). The gene encoding cystathionine β-synthase ( Cbs ), which is involved in the methionine/cysteine cycle, is overexpressed in the DS brain ( Ichinohe et al, 2005 ).…”

Section: Identification Of Molecular Mechanisms and Candidate Genes Fmentioning

confidence: 99%

Rodent models in Down syndrome research: impact and future opportunities

Hérault

Delabar

Fisher

et al. 2017

Disease Models &Amp; Mechanisms

166

182

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Down syndrome is caused by trisomy of chromosome 21. To date, a multiplicity of mouse models with Down-syndrome-related features has been developed to understand this complex human chromosomal disorder. These mouse models have been important for determining genotype-phenotype relationships and identification of dosage-sensitive genes involved in the pathophysiology of the condition, and in exploring the impact of the additional chromosome on the whole genome. Mouse models of Down syndrome have also been used to test therapeutic strategies. Here, we provide an overview of research in the last 15 years dedicated to the development and application of rodent models for Down syndrome. We also speculate on possible and probable future directions of research in this fast-moving field. As our understanding of the syndrome improves and genome engineering technologies evolve, it is necessary to coordinate efforts to make all Down syndrome models available to the community, to test therapeutics in models that replicate the whole trisomy and design new animal models to promote further discovery of potential therapeutic targets.

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Section: Identification Of Molecular Mechanisms and Candidate Genes Fmentioning

confidence: 99%

Rodent models in Down syndrome research: impact and future opportunities

Hérault

Delabar

Fisher

et al. 2017

Disease Models &Amp; Mechanisms

166

182

View full text Add to dashboard Cite

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“…In addition, Ts65Dn mice display alterations in dendritic spine morphology (Belichenko et al, 2004; Guidi et al, 2013) and impaired neurogenesis both in the developing brain (Baxter et al, 2000; Roper et al, 2006; Chakrabarti et al, 2007, 2010; Contestabile et al, 2007, 2009) and in neurogenic niches of the adult brain (Clark et al, 2006; Bianchi et al, 2010a; Contestabile et al, 2013). Additionally, Ts65Dn mice are not spontaneously epileptic, but show increased seizures incidence in some experimental epilepsy paradigms (Cortez et al, 2009; Westmark et al, 2010; Joshi et al, 2016). Finally, similarly to DS patients, Ts65Dn mice also exhibit some sleep alterations and hyperactivity in locomotor behavior (Escorihuela et al, 1995; Reeves et al, 1995; Sago et al, 2000; Colas et al, 2008).…”

Section: Mouse Models Of Dsmentioning

confidence: 99%

“…This increase of GABA B /GIRK signaling in Ts65Dn neurons could strongly affect neuronal excitability and plasticity by enhancement of GIRK-mediated shunting inhibition, reduction of excitatory PSPs, back-propagating action potentials, and change of neuronal passive properties (Lüscher et al, 1997; Koyrakh et al, 2005). Anyhow, genetically restoring GIRK2 gene dosage to disomy in Ts65Dn mice (by crossing to GIRK2 +/− mice) rescued the observed increase in GABA B -triggered currents in CA1 pyramidal neurons (Joshi et al, 2016). In agreement with triplication of KCNJ6 and the increase of GABA B /GIRK signaling, V REST is hyperpolarized by 2.3 mV in CA1 pyramidal neurons and by 6.2 mV in DG granule cells (DGGC; Best et al, 2012; Kleschevnikov et al, 2012b).…”

Section: Gaba Signaling In Ds Mouse Modelsmentioning

confidence: 99%

“…However, the increased incidence of seizures is in line with depolarizing GABA A signaling in DS, because the shift in GABA A R-mediated responses will also clearly impact on the excitatory/inhibitory balance and promote brain neuronal circuit hyperexcitability. Interestingly, administration of γ-butyrolactone (GBL, a prodrug for the GABA B R agonist γ-hydroxybutyrate: GHB) induced epileptiform activity in Ts65Dn mice that was rescued by genetically restoring GIRK2 gene dosage to disomy (Cortez et al, 2009; Joshi et al, 2016). Although the general molecular mechanism of GHB action is still matter of debate (Bay et al, 2014; Venzi et al, 2015), it is intriguing to speculate that, in the scenario of GABA dysregulation in DS, both the GABA B R-GIRK2 signaling and depolarizing GABA A signaling may play a role in GBL-induced epileptic phenotype seen in Ts65Dn mice.…”

Section: Speculation For Future Directions In the Research On Ds And mentioning

confidence: 99%

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The GABAergic Hypothesis for Cognitive Disabilities in Down Syndrome

Contestabile

Magara

Cancedda

2017

Front. Cell. Neurosci.

107

105

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Down syndrome (DS) is a genetic disorder caused by the presence of a third copy of chromosome 21. DS affects multiple organs, but it invariably results in altered brain development and diverse degrees of intellectual disability. A large body of evidence has shown that synaptic deficits and memory impairment are largely determined by altered GABAergic signaling in trisomic mouse models of DS. These alterations arise during brain development while extending into adulthood, and include genesis of GABAergic neurons, variation of the inhibitory drive and modifications in the control of neural-network excitability. Accordingly, different pharmacological interventions targeting GABAergic signaling have proven promising preclinical approaches to rescue cognitive impairment in DS mouse models. In this review, we will discuss recent data regarding the complex scenario of GABAergic dysfunctions in the trisomic brain of DS mice and patients, and we will evaluate the state of current clinical research targeting GABAergic signaling in individuals with DS.

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“…The overexpression of GIRK2 is necessary for the production of the IS-like phenotype, as the knockdown of the Kcnj6 gene (which codes for GIRK2) made the mice resistant to GABA B agonist-induced spasms [42,43]. However, trisomy of Kcnj6 is not sufficient for replicating the desired phenotype.…”

Section: Excessive Gaba B Receptor-mediated Potassium Currents: Ts65dmentioning

confidence: 99%

Infantile Spasms: An Update on Pre-Clinical Models and EEG Mechanisms

Janicot¹,

Shao²,

Stafstrom³

2020

Children

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Infantile spasms (IS) is an epileptic encephalopathy with unique clinical and electrographic features, which affects children in the middle of the first year of life. The pathophysiology of IS remains incompletely understood, despite the heterogeneity of IS etiologies, more than 200 of which are known. In particular, the neurobiological basis of why multiple etiologies converge to a relatively similar clinical presentation has defied explanation. Treatment options for this form of epilepsy, which has been described as “catastrophic” because of the poor cognitive, developmental, and epileptic prognosis, are limited and not fully effective. Until the pathophysiology of IS is better clarified, novel treatments will not be forthcoming, and preclinical (animal) models are essential for advancing this knowledge. Here, we review preclinical IS models, update information regarding already existing models, describe some novel models, and discuss exciting new data that promises to advance understanding of the cellular mechanisms underlying the specific EEG changes seen in IS—interictal hypsarrhythmia and ictal electrodecrement.

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

Abstract: 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;80:511-521.

Cited by 22 publications

References 48 publications

Rodent models in Down syndrome research: impact and future opportunities

Rodent models in Down syndrome research: impact and future opportunities

The GABAergic Hypothesis for Cognitive Disabilities in Down Syndrome

Infantile Spasms: An Update on Pre-Clinical Models and EEG Mechanisms

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