Down-Regulation of Astrocytic Kir4.1 Channels during the Audiogenic Epileptogenesis in Leucine-Rich Glioma-Inactivated 1 (Lgi1) Mutant Rats

Kinboshi, Masato; Shimizu, Saki; Mashimo, Tomoji; Serikawa, Tadao; Ito, Hidefumi; Ikeda, Akio; Takahashi, Ryōsuke; Ohno, Yukihiro

doi:10.3390/ijms20051013

Cited by 22 publications

(29 citation statements)

References 46 publications

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“…In NER, Kir4.1 expression was region-specifically reduced in the amygdala, where the expression of Fos protein, a biological marker of neural excitation, significantly elevated ( 89 ). Moreover, Leucine-Rich Glioma-Inactivated 1 (Lgi1) mutant rats, a model of human autosomal dominant lateral temporal lobe epilepsy (ADLTE), showed reduced astrocytic Kir4.1 expression in specific regions, including both the lateral and medial temporal lobes, after the acquisition of audiogenic seizure susceptibility ( Table 1 ) ( 96 ). In these regions, neural hyperexcitation during seizures was confirmed using Fos immunohistochemical techniques ( 97 ).…”

Section: Kir41 Channels In Animal Epilepsy Modelsmentioning

confidence: 99%

“…Auditory stimuli for seizure induction consisted of sound stimulation twice, priming stimulation at P16 and test stimulation at 8 weeks. Priming stimulation induces epileptogenesis caused by Lgi1 mutation without spontaneous seizure phenotypes ( 96 , 98 ). Interestingly, the Kir4.1 expression in astrocytes was reduced during the time-course of epileptogenesis before application of test stimulation at the age of 8 weeks in Lgi1 mutant rats ( 96 ).…”

Section: Kir41 Channels In Animal Epilepsy Modelsmentioning

confidence: 99%

“…Priming stimulation induces epileptogenesis caused by Lgi1 mutation without spontaneous seizure phenotypes ( 96 , 98 ). Interestingly, the Kir4.1 expression in astrocytes was reduced during the time-course of epileptogenesis before application of test stimulation at the age of 8 weeks in Lgi1 mutant rats ( 96 ). These findings indicate that the dysfunction of Kir4.1 channels is involved not only in evoking seizure generation, but also in chronic development of epilepsy (epileptogenesis).…”

Section: Kir41 Channels In Animal Epilepsy Modelsmentioning

confidence: 99%

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Role of Astrocytic Inwardly Rectifying Potassium (Kir) 4.1 Channels in Epileptogenesis

2020

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Astrocytes regulate potassium and glutamate homeostasis via inwardly rectifying potassium (Kir) 4.1 channels in synapses, maintaining normal neural excitability. Numerous studies have shown that dysfunction of astrocytic Kir4.1 channels is involved in epileptogenesis in humans and animal models of epilepsy. Specifically, Kir4.1 channel inhibition by KCNJ10 gene mutation or expressional down-regulation increases the extracellular levels of potassium ions and glutamate in synapses and causes hyperexcitation of neurons. Moreover, recent investigations demonstrated that inhibition of Kir4.1 channels facilitates the expression of brain-derived neurotrophic factor (BDNF), an important modulator of epileptogenesis, in astrocytes. In this review, we summarize the current understanding on the role of astrocytic Kir4.1 channels in epileptogenesis, with a focus on functional and expressional changes in Kir4.1 channels and their regulation of BDNF secretion. We also discuss the potential of Kir4.1 channels as a therapeutic target for the prevention of epilepsy.

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Section: Kir41 Channels In Animal Epilepsy Modelsmentioning

confidence: 99%

Section: Kir41 Channels In Animal Epilepsy Modelsmentioning

confidence: 99%

Section: Kir41 Channels In Animal Epilepsy Modelsmentioning

confidence: 99%

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Role of Astrocytic Inwardly Rectifying Potassium (Kir) 4.1 Channels in Epileptogenesis

2020

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“…For example, astrocyte-specific deletion of K ir 4.1, an inwardly rectifying potassium channel, impairs potassium ion transfer and glutamate uptake by astrocytes, causing seizures, ataxia and premature death in mice [ 54 ]. In addition, down-regulation of astrocytic Kir4.1 in some brain regions were reported in rodent epilepsy models [ 55 , 56 ]. These findings suggest that disruption of spatial potassium-buffering function of astrocytes is involved in the development of epilepsy.…”

Section: Animal and Patient-derived Ipsc Models For Epilepsy Reseamentioning

confidence: 99%

Investigating Developmental and Epileptic Encephalopathy Using Drosophila melanogaster

Takai

Yamaguchi

Yoshida

et al. 2020

IJMS

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Developmental and epileptic encephalopathies (DEEs) are the spectrum of severe epilepsies characterized by early-onset, refractory seizures occurring in the context of developmental regression or plateauing. Early infantile epileptic encephalopathy (EIEE) is one of the earliest forms of DEE, manifesting as frequent epileptic spasms and characteristic electroencephalogram findings in early infancy. In recent years, next-generation sequencing approaches have identified a number of monogenic determinants underlying DEE. In the case of EIEE, 85 genes have been registered in Online Mendelian Inheritance in Man as causative genes. Model organisms are indispensable tools for understanding the in vivo roles of the newly identified causative genes. In this review, we first present an overview of epilepsy and its genetic etiology, especially focusing on EIEE and then briefly summarize epilepsy research using animal and patient-derived induced pluripotent stem cell (iPSC) models. The Drosophila model, which is characterized by easy gene manipulation, a short generation time, low cost and fewer ethical restrictions when designing experiments, is optimal for understanding the genetics of DEE. We therefore highlight studies with Drosophila models for EIEE and discuss the future development of their practical use.

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“…The main function of Kir4.1 is to carry potassium ions into cells accompanied by water entry through AQP4, which could reduce the excitability of neurons. 10,11 In epilepsy, water homeostasis and ion concentration regulation imbalance of ECS may also lead to reduced sensitivity to AEDs and generate drug resistance. AQP4 was found to be significantly increased in protein levels in surgical resection from patients with refractory temporal lobe epilepsy (TLE), suggesting that AQP4 may be associated with epileptic drug resistance.…”

Section: Introductionmentioning

confidence: 99%

<p>Effects of AQP4 and KCNJ10 Gene Polymorphisms on Drug Resistance and Seizure Susceptibility in Chinese Han Patients with Focal Epilepsy</p>

Zhu¹,

Zhang²,

Fu³

et al. 2020

NDT

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Background and Purpose: Epilepsy is a common chronic neurological disorder. About one third of epilepsy patients will suffer from drug resistance after rational selection of antiepileptic drug treatment. The formation of drug-resistant epilepsy has quite a few causes of which genetic factors are considered to be the most important. Previous studies have suggested that the aquaporin 4(AQP4) and inward rectifier potassium ion channel Kir4.1 (encoded by gene KCNJ10) may act in concert to adjust water homeostasis and concentration of potassium ions in extracellular spaces of the central nervous system. Therefore, these two molecules would play a major role in the regulation of the excitability of neurons. In order to explore the potential mechanism of genetic factors related to AQP4 and Kir4.1, we conducted a study to analyze the effects of the AQP4 and KCNJ10 genes' single nucleotide polymorphisms (SNPs) on epileptic drug resistance and seizure susceptibility in a group of Chinese Han patients with focal epilepsy. Materials and Methods: In total, 510 patients with focal-onset seizures and 206 healthy controls were recruited. Among the patients, 222 were drug resistant and 288 were responsive. The selection of tag SNPs was based on the Hapmap database and Haploview software. Genotyping of three loci of the AQP4 gene (rs1058424, rs3763043 and rs35931) and nine loci of the KCNJ10 gene (rs12122979, rs1186685, rs6690889, rs2486253, rs1186675, rs12402969, rs12729701, rs1890532 and rs3795339) was conducted on the Sequenom MassARRAY iPLEX platform. Results: The distribution of genotype and allele frequencies of selected SNP loci of AQP4 and KCNJ10 genes showed no significant difference between the drug-resistant and drugresponsive groups (p>0.05), and no significant difference between all the idiopathic focal epilepsy patients and healthy controls either. Conclusion: AQP4 and KCNJ10 genetic polymorphisms may not be associated with drug resistance or seizure susceptibility of focal epilepsy in the Chinese Han population.

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Down-Regulation of Astrocytic Kir4.1 Channels during the Audiogenic Epileptogenesis in Leucine-Rich Glioma-Inactivated 1 (Lgi1) Mutant Rats

Cited by 22 publications

References 46 publications

Role of Astrocytic Inwardly Rectifying Potassium (Kir) 4.1 Channels in Epileptogenesis

Role of Astrocytic Inwardly Rectifying Potassium (Kir) 4.1 Channels in Epileptogenesis

Investigating Developmental and Epileptic Encephalopathy Using Drosophila melanogaster

<p>Effects of AQP4 and KCNJ10 Gene Polymorphisms on Drug Resistance and Seizure Susceptibility in Chinese Han Patients with Focal Epilepsy</p>

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