Potassium channel activity and glutamate uptake are impaired in astrocytes of seizure‐susceptible DBA/2 mice

Abstract

Summary Purpose KCNJ10 encodes subunits of inward rectifying potassium (Kir) channel Kir4.1 found predominantly in glial cells within the brain. Genetic inactivation of these channels in glia impairs extracellular K+ and glutamate clearance and produces a seizure phenotype. In both mice and humans, polymorphisms and mutations in the KCNJ10 gene have been associated with seizure susceptibility. The purpose of the present study was to determine whether there are differences in Kir channel activity and potassium and glutamate buffering capabilities between astrocytes from seizure resistant C57BL/6 (B6) and seizure susceptible DBA/2 (D2) mice that are consistent with an altered K+ channel activity as a result of genetic polymorphism of KCNJ10. Methods Using cultured astrocytes and hippocampal brain slices together with whole-cell patch-clamp, we determined the electrophysiological properties, particularly K+ conductances, of B6 and D2 mouse astrocytes. Using a colorimetric assay, we determined glutamate clearance capacity by B6 and D2 astrocytes. Results Barium-sensitive Kir currents elicited from B6 astrocytes are substantially larger than those elicited from D2 astrocytes. In addition, potassium and glutamate buffering by D2 cortical astrocytes is impaired, relative to buffering by B6 astrocytes. Discussion In summary, the activity of Kir4.1 channels differs between seizure susceptible D2 and seizure resistant B6 mice. Reduced activity of Kir4.1 channels in astrocytes of D2 mice is associated with deficits in potassium and glutamate buffering. These deficits may, in part, explain the relatively low seizure threshold of D2 mice.

Genetically epilepsy-prone rats (GEPRs) and DBA/2 mice: Two animal models of audiogenic reflex epilepsy for the evaluation of new generation AEDs

“…In astrocytes of DBA/2 mice, there is reduced activity of inward rectifying potassium (Kir) 4.1 channels accompanied by deficits in K + and glutamate buffering. These deficits may, in part, explain the relatively low seizure threshold of DBA/2 mice in comparison to C57BL/6 mice [57].…”

Astrocyte dysfunction in temporal lobe epilepsy: K+ channels and gap junction coupling

“…Comparative electrophysiological analysis of seizure-resistant (B6) and seizure-susceptible (D2) mice, which differ at position 262 of KCNJ10, revealed a profound reduction of Ba 21 -sensitive Kir currents in the latter (Inyushin et al, 2010). Astrocytes from D2 mice also displayed impaired glutamate clearance.…”

Molecular Mechanisms of EAST/SeSAME Syndrome Mutations in Kir4.1 (KCNJ10)

“…Polymorphisms in the KCNJ10 gene have been associated with decreased astrocytic Kir channel currents (26), seizure susceptibility, and epilepsy (27)(28)(29)(30), but biophysical characterization of these variants failed to show effects on Kir4.1 channel properties (31). More recently, two independent studies described a novel syndrome, termed EAST or SeSAME, that presents with a unique set of symptoms including epilepsy, ataxia, mental retardation, hearing loss, and electrolyte imbalance related to renal salt loss (32,33).…”