Absence-like seizures and their pharmacological profile in tottering-6j mice

Kim, Tae Yeon; Maki, Takehiro; Zhou, Ying; Sakai, Keita; Mizuno, Yuri; Ishikawa, Akiyoshi; Tanaka, Ryo; Niimi, Kimie; Li, Weidong; Nagano, Norihiro; Takahashi, Eiki

doi:10.1016/j.bbrc.2015.05.050

Cited by 14 publications

(17 citation statements)

References 18 publications

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“…Frequent SWDs in rodent models is indicative of absence seizures (Akman et al, 2010;Kim et al, 2015;Tokuda et al, 2007), which are usually accompanied by behavioral arrest (Frankel et al, 2005;Pearce et al, 2014;Tan et al, 2007). We used a camera synchronized to the EEG with automated tracking to record mouse movement and observed that movement correlated with inter-SWD interval duration, and inversely correlated with SWD duration, demonstrating some behavioral arrest during the longest SWD events ( Figure 2H).…”

Section: Excitability Phenotypes In Gnb1 K78r/+ Micementioning

confidence: 97%

“…Owing to the short half-life of both drugs, SWDs progressively recovered an hour after treatment. On the other hand, phenytoin (PHT), an AED with a probable worsening effect on absence seizures in humans and rodents (Kim et al, 2015;Manning et al, 2003;Marescaux et al, 1992;Vrielynck, 2013), did not affect SWD occurrence ( Figure 4A).…”

Section: Pharmacological Response Of the Pre-clinical Modelsmentioning

confidence: 99%

“…Ethosuximide (ETX) and valproic acid (VPA) are two antiepileptic drugs (AED) commonly used to treat absence seizures in humans, which also interrupt SWDs rodent models (Kim et al, 2015;Manning et al, 2003;Marescaux et al, 1992;Vrielynck, 2013). Acute treatment of Gnb1 K78R/+ mice with either ETX or VPA nearly abolished SWDs ( Figure 4A).…”

Section: Pharmacological Response Of the Pre-clinical Modelsmentioning

confidence: 99%

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G protein-coupled potassium channels implicated in mouse and cellular models of GNB1 Encephalopathy

Colombo

Petri

Shalomov

et al. 2019

Preprint

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De novo mutations in GNB1, encoding the Gβ1 subunit of G proteins, cause a neurodevelopmental disorder with global developmental delay and epilepsy. Mice carrying a pathogenic mutation, K78R, recapitulate aspects of the disorder, including developmental delay and frequent spike-wave discharges (SWD). Cultured mutant cortical neurons display aberrant bursting activity on multi-electrode arrays. Strikingly, the antiepileptic drug ethosuximide (ETX) restores normal neuronal network behavior in vitro and suppresses SWD in vivo. In contrast, while valproic acid suppresses SWD, it does not restore normal network behavior, suggesting that ETX has mechanistic specificity for the effects of aberrant Gβ1 signaling. Consistent with this, we show that K78R is a gain-of-function of G protein-coupled potassium channel (GIRK) activation that is potently inhibited by ETX. This work suggests that altered Gβ1 signaling causes disease in part through effects on GIRK channels, illustrates the utility of cultured neuronal networks in pharmacological screening, and establishes effective pre-clinical models for GNB1 Encephalopathy.

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Section: Excitability Phenotypes In Gnb1 K78r/+ Micementioning

confidence: 97%

Section: Pharmacological Response Of the Pre-clinical Modelsmentioning

confidence: 99%

Section: Pharmacological Response Of the Pre-clinical Modelsmentioning

confidence: 99%

See 1 more Smart Citation

G protein-coupled potassium channels implicated in mouse and cellular models of GNB1 Encephalopathy

Colombo

Petri

Shalomov

et al. 2019

Preprint

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“…Moreover, early-onset epileptic encephalopathy has been described in humans [9,10,16]. Additionally, CACNA1A mutations have been detected in rodents [17][18][19] and humans suffering from absence seizures with/without cerebellar ataxia [13,20,21].…”

Section: Introductionmentioning

confidence: 99%

Phenotypic Characterization of Larval Zebrafish (Danio rerio) with Partial Knockdown of the cacna1a Gene

et al. 2019

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The CACNA1A gene encodes the pore-forming α1 subunit of voltage-gated P/Q type Ca 2+ channels (Ca v 2.1). Mutations in this gene, among others, have been described in patients and rodents suffering from absence seizures and episodic ataxia type 2 with/ without concomitant seizures. In this study, we aimed for the first time to assess phenotypic and behavioral alterations in larval zebrafish with partial cacna1aa knockdown, placing special emphasis on changes in epileptiform-like electrographic discharges in larval brains. Whole-mount in situ hybridization analysis revealed expression of cacna1aa in the optic tectum and medulla oblongata of larval zebrafish at 4 and 5 days post-fertilization. Next, microinjection of two antisense morpholino oligomers (individually or in combination) targeting all splice variants of cacna1aa into fertilized zebrafish eggs resulted in dose-dependent mortality and decreased or absent touch response. Over 90% knockdown of cacna1aa on protein level induced epileptiform-like discharges in the optic tectum of larval zebrafish brains. Incubation of morphants with antiseizure drugs (sodium valproate, ethosuximide, lamotrigine, topiramate) significantly decreased the number and, in some cases, cumulative duration of epileptiform-like discharges. In this context, sodium valproate seemed to be the least effective. Carbamazepine did not affect the number and duration of epileptiform-like discharges. Altogether, our data indicate that cacna1aa loss-of-function zebrafish may be considered a new model of absence epilepsy and may prove useful both for the investigation of Cacna1a-mediated epileptogenesis and for in vivo drug screening.

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“…Susceptibility to CSD is also increased in S218L mutant mice 11,21,22. A CACNA1A gene knock-in mouse model (6J-Tg) is a typical absence seizure animal model;23 we found that patients with absence seizures have a CACNA1A mutation 16,24. In 6J-Tg mice, the amino acid sequences of the S4–S5 connecting area, the S5, and part of the S5–S6 connecting region also have a high number of mutations 25.…”

Section: Cacna1a Genementioning

confidence: 99%

The genetic relationship between epilepsy and hemiplegic migraine

Huang¹,

Xiao²,

Qin³

et al. 2017

NDT

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Epilepsy and migraine are common diseases of the nervous system and share genetic and pathophysiological mechanisms. Familial hemiplegic migraine is an autosomal dominant disease. It is often used as a model of migraine. Four genes often contain one or more mutations in both epilepsy and hemiplegic migraine patients (ie, CACNA1A, ATP1A2, SCN1A, and PRRT2). A better understanding of the shared genetics of epilepsy and hemiplegic migraine may reveal new strategic directions for research and treatment of both the disorders.

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Absence-like seizures and their pharmacological profile in tottering-6j mice

Cited by 14 publications

References 18 publications

G protein-coupled potassium channels implicated in mouse and cellular models of GNB1 Encephalopathy

G protein-coupled potassium channels implicated in mouse and cellular models of GNB1 Encephalopathy

Phenotypic Characterization of Larval Zebrafish (Danio rerio) with Partial Knockdown of the cacna1a Gene

The genetic relationship between epilepsy and hemiplegic migraine

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