Abstract
The dysfunction of astrocytic inwardly rectifying potassium (Kir) 4.1 channels, which mediate the spatial potassium-buffering function of astrocytes, is known to be involved in the development of epilepsy. Here, we analyzed the Kir4.1 expressional changes in Leucine-Rich Glioma-Inactivated 1 (Lgi1) mutant rats, which is a model of autosomal dominant lateral temporal lobe epilepsy in humans, to clarify the role of astrocytic Kir4.1 channels in Lgi1-related epileptogenesis. Priming acoustic stimulation (at postnatal day 16) conferred seizure susceptibility on Lgi1 mutant rats, which evoked audiogenic seizures with test stimulation at eight weeks. In the seizure-susceptible Lgi1 mutant rats (before test stimulation), astrocytic Kir4.1 expression was down-regulated region-specifically in the cerebral cortex, hippocampus, and amygdala. In addition, prophylactic treatments of Lgi1 mutant rats with valproic acid (VPA, 30 mg/kg and 200 mg/kg) for two weeks prevented both the development of seizure susceptibility and the down-regulation of Kir4.1 expression in astrocytes. The present study demonstrated for the first time that the astrocytic Kir4.1 expression was reduced in the Lgi1-related seizure model, suggesting that the down-regulation of Kir4.1 channels in astrocytes is involved in audiogenic epileptogenesis caused by Lgi1 mutation. In addition, VPA seemed to have a prophylactic effect on Lgi1-related seizures.
Highlights
Astrocytes are a major component of glial cells in the brain that form tripartite synapses in conjunction with neuronal components, and actively regulate the excitability and plasticity of neurons
We previously showed that the inhibition of Kir4.1 channels facilitated the expression of brain-derived neurotrophic factor (BDNF) in astrocytes, which has long been implicated in the development of epilepsy [18,19]
We evaluated the Kir4.1 expressional changes in astrocytes during the development of audiogenic epilepsy in Leucine-Rich Glioma-Inactivated 1 (Lgi1) mutant rats to clarify the potential involvement of astrocytic Kir4.1 channels in Lgi1-related epileptogenesis
Summary
Astrocytes are a major component of glial cells in the brain that form tripartite synapses in conjunction with neuronal components (presynaptic nerve terminal and postsynaptic neuronal membrane), and actively regulate the excitability and plasticity of neurons. Previous studies using conditional knockout mice have shown that the specific deletion of Kir4.1 in astrocytes depolarized their resting membrane potential and markedly reduced the transport capacity of K+ and glutamate into astrocytes, causing ataxia, epileptic symptoms, and early mortality [9]. These findings suggest that disruption of the spatial K+ buffering function of astrocytes is associated with the induction of motor disorders, including epilepsy. We studied the prophylactic actions of VPA in Lgi1-related epileptogenesis, with a focus on its regulation of Kir4.1 channel expression
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