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

Int J Mol Sci. 2019 Feb 26;20(5):1013. doi: 10.3390/ijms20051013.

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.

Keywords: ADLTE; Kir4.1 channels; Lgi1; antiepileptics; astrocytes; epilepsy; valproic acid.

MeSH terms

  • Acoustics
  • Animals
  • Astrocytes / metabolism*
  • Disease Susceptibility
  • Down-Regulation*
  • Epilepsy, Reflex / drug therapy
  • Epilepsy, Reflex / genetics*
  • Glial Fibrillary Acidic Protein / metabolism
  • Intercellular Signaling Peptides and Proteins
  • Male
  • Mutation / genetics*
  • Potassium Channels, Inwardly Rectifying / genetics*
  • Potassium Channels, Inwardly Rectifying / metabolism
  • Proteins / genetics*
  • Proteins / metabolism
  • Rats, Inbred F344
  • Valproic Acid / pharmacology
  • Valproic Acid / therapeutic use

Substances

  • Glial Fibrillary Acidic Protein
  • Intercellular Signaling Peptides and Proteins
  • Kcnj10 (channel)
  • Lgi1 protein, rat
  • Potassium Channels, Inwardly Rectifying
  • Proteins
  • Valproic Acid