Expressional Analysis of Inwardly Rectifying Kir4.1 Channels in Groggy Rats, a Rat Model of Absence Seizures

Harada, Yuya; Nagao, Yuki; Mukai, Takahiro; Shimizu, Saki; Tokudome, Kentaro; Kunisawa, Naofumi; Serikawa, Tadao; Sasa, Masashi; Ohno, Yukihiro

doi:10.5812/archneurosci.18651

Cited by 5 publications

(6 citation statements)

References 32 publications

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“…Therefore, Kir4.1 channels may not be involved in preventive effects of ethosuximide on absence seizures. This is consistent with our previous findings that down-regulation of Kir4.1 expression was observed only in the GTCSs model (e.g., Noda epileptic rats), but not in the absence seizure model (Groggy rats), implying that pathophysiological alterations of Kir4.1 are not linked to non-convulsive absence seizures (Harada et al, 2013 , 2014 ; Ohno et al, 2015 ).…”

Section: Discussionsupporting

confidence: 92%

Antiepileptic Drugs Elevate Astrocytic Kir4.1 Expression in the Rat Limbic Region

et al. 2018

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Inwardly rectifying potassium (Kir) channel subunits Kir4.1 are specifically expressed in astrocytes and regulate neuronal excitability by mediating spatial potassium buffering. In addition, it is now known that astrocytic Kir4.1 channels are closely involved in the pathogenesis of epilepsy. Here, to explore the role of Kir4.1 channels in the treatment of epilepsy, we evaluated the effects of the antiepileptic drugs, valproate, phenytoin, phenobarbital and ethosuximide, on Kir4.1 expression in astrocytes using immunohistochemical techniques. Repeated treatment of rats with valproate (30–300 mg/kg, i.p., for 1–10 days) significantly elevated the Kir4.1 expression levels in the cerebral cortex, amygdala and hippocampus. Up-regulation of Kir4.1 expression by valproate occurred in a dose- and treatment period-related manner, and did not accompany an increase in the number of astrocytes probed by glial fibrillary acidic protein (GFAP). In addition, repeated treatment with phenytoin (30 mg/kg, i.p., for 10 days) or phenobarbital (30 mg/kg, i.p., for 10 days) also elevated Kir4.1 expression region-specifically in the amygdala. However, ethosuximide (100 mg/kg, i.p., for 10 days), which can alleviate absence but not convulsive seizures, showed no effects on the astrocytic Kir4.1 expression. The present results demonstrated for the first time that the antiepileptic drugs effective for convulsive seizures (valproate, phenytoin, and phenobarbital) commonly elevate the astrocytic Kir4.1 channel expression in the limbic regions, which may be related to their antiepileptic actions.

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Section: Discussionsupporting

confidence: 92%

Antiepileptic Drugs Elevate Astrocytic Kir4.1 Expression in the Rat Limbic Region

et al. 2018

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“…The high baseline K + concentration in astrocytes is due to the normal function of the Na + /K + -ATPase pump. In particular, spontaneous epileptic activity was directly induced in the single astrocyte-neuron network module without external stimuli when the conductance of Kir4.1 channels was lower than a certain threshold, further demonstrating that down-regulation of astrocytic Kir4.1 channels is closely related to neuropathological hyper-excitability [ 8 , 45 , 46 ]. At the same time, our single astrocyte-neuron network correctly predicts that when there is a partial blockage of Kir4.1 channels in astrocytes, rapid instantaneous neuronal seizure activity is induced.…”

Section: Discussionmentioning

confidence: 99%

Astrocytic Kir4.1 channels and gap junctions account for spontaneous epileptic seizure

Chen

et al. 2018

PLoS Comput Biol

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Experimental recordings in hippocampal slices indicate that astrocytic dysfunction may cause neuronal hyper-excitation or seizures. Considering that astrocytes play important roles in mediating local uptake and spatial buffering of K+ in the extracellular space of the cortical circuit, we constructed a novel model of an astrocyte-neuron network module consisting of a single compartment neuron and 4 surrounding connected astrocytes and including extracellular potassium dynamics. Next, we developed a new model function for the astrocyte gap junctions, connecting two astrocyte-neuron network modules. The function form and parameters of the gap junction were based on nonlinear regression fitting of a set of experimental data published in previous studies. Moreover, we have created numerical simulations using the above single astrocyte-neuron network module and the coupled astrocyte-neuron network modules. Our model validates previous experimental observations that both Kir4.1 channels and gap junctions play important roles in regulating the concentration of extracellular potassium. In addition, we also observe that changes in Kir4.1 channel conductance and gap junction strength induce spontaneous epileptic activity in the absence of external stimuli.

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“…Finally, in contrast to the above described animal models with convulsive seizures, no expressional alterations to Kir4.1 were observed in Groggy rats, an animal model of absence seizures [47] (Table 1). These results suggest a distinct role of Kir4.1 channels and spatial K + buffering in modulating convulsive seizures (e.g., GTCS and TLE seizures) vs. non-convulsive absence seizures.…”

Section: Structure and Drug Interaction Of Kir41 Channelsmentioning

confidence: 95%

Role of astroglial Kir4.1 channels in the pathogenesis and treatment of epilepsy

Ohno

Tokudome²,

Kunisawa³

et al. 2015

Ther Targets Neurol Dis

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The inwardly rectifying potassium (Kir) channel subunit Kir4.1 is specifically expressed in brain astrocytes and Kir4.1-containing channels (Kir4.1 channels) mediate astroglial spatial potassium (K + ) buffering. Recent advances in Kir4.1 research revealed that Kir4.1 channels can serve as a novel therapeutic target for epilepsy. Specifically, reduced expression or dysfunction of Kir4.1 channels seems to be involved in generation of generalized tonic-clonic seizures (GTCS) in animal models of epilepsy and patients with temporal lobe epilepsy. In addition, recent clinical studies showed that loss-of-function mutations of human gene (KCNJ10) encoding Kir4.1 elicit "EAST" or "SeSAME" syndrome which manifests as GTCS and ataxia. Although the precise mechanisms remain to be clarified, it is suggested that dysfunction of Kir4.1 channels disrupts spatial K + buffering by astrocytes, elevates extracellular levels of K + and/or glutamate and causes abnormal excitation of neurons in the limbic regions and neocortex. All these findings suggest that agents that activate or up-regulate astroglial Kir4.1 channels would be effective for epilepsy. In addition, docking simulation analysis using the Kir4.1 homology model provides important information for designing new Kir4.1 ligands. Discovery of such agents that activate or up-regulate Kir4.1 channels would be a novel approach for the treatment of epilepsy.

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Expressional Analysis of Inwardly Rectifying Kir4.1 Channels in Groggy Rats, a Rat Model of Absence Seizures

Cited by 5 publications

References 32 publications

Antiepileptic Drugs Elevate Astrocytic Kir4.1 Expression in the Rat Limbic Region

Antiepileptic Drugs Elevate Astrocytic Kir4.1 Expression in the Rat Limbic Region

Astrocytic Kir4.1 channels and gap junctions account for spontaneous epileptic seizure

Role of astroglial Kir4.1 channels in the pathogenesis and treatment of epilepsy

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