Abstract
The inwardly rectifying potassium (Kir) channel Kir4.1 in brain astrocytes mediates spatial K+ buffering and regulates neural activities. Recent studies have shown that loss-of-function mutations in the human gene KCNJ10 encoding Kir4.1 cause epileptic seizures, suggesting a close relationship between the Kir4.1 channel function and epileptogenesis. Here, we performed expressional analysis of Kir4.1 in a pilocarpine-induced rat model of temporal lobe epilepsy (TLE) to explore the role of Kir4.1 channels in modifying TLE epileptogenesis. Treatment of rats with pilocarpine (350 mg/kg, i.p.) induced acute status epilepticus, which subsequently caused spontaneous seizures 7–8 weeks after the pilocarpine treatment. Western blot analysis revealed that TLE rats (interictal condition) showed significantly higher levels of Kir4.1 than the control animals in the cerebral cortex, striatum, and hypothalamus. However, the expression of other Kir subunits, Kir5.1 and Kir2.1, remained unaltered. Immunohistochemical analysis illustrated that Kir4.1-immunoreactivity-positive astrocytes in the pilocarpine-induced TLE model were markedly increased in most of the brain regions examined, concomitant with an increase in the number of glial fibrillary acidic protein (GFAP)-positive astrocytes. In addition, Kir4.1 expression ratios relative to the number of astrocytes (Kir4.1-positive cells/GFAP-positive cells) were region-specifically elevated in the amygdala (i.e., medial and cortical amygdaloid nuclei) and sensory cortex. The present study demonstrated for the first time that the expression of astrocytic Kir4.1 channels was elevated in a pilocarpine-induced TLE model, especially in the amygdala, suggesting that astrocytic Kir4.1 channels play a role in modifying TLE epileptogenesis, possibly by acting as an inhibitory compensatory mechanism.
Highlights
The spatial K+ buffering by astrocytes removes excess extracellular K+ at synapses and transports them into regions of low K+ concentration such as blood vessels, regulating neuronal activities (Walz, 2000; Kofuji and Newman, 2004; Simard and Nedergaard, 2004; Butt and Kalsi, 2006)
The present study demonstrated for the first time that the expression of astrocytic Kir4.1 channels was elevated in a pilocarpine-induced temporal lobe epilepsy (TLE) model, especially in the amygdala, suggesting that astrocytic Kir4.1 channels play a role in modifying TLE epileptogenesis, possibly by acting as an inhibitory compensatory mechanism
The present study demonstrated for the first time that expression of astrocytic Kir4.1 channels mediating spatial K+ buffering was markedly elevated in a pilocarpine-induced TLE model
Summary
The spatial K+ buffering by astrocytes removes excess extracellular K+ at synapses and transports them into regions of low K+ concentration such as blood vessels, regulating neuronal activities (Walz, 2000; Kofuji and Newman, 2004; Simard and Nedergaard, 2004; Butt and Kalsi, 2006). The K+ buffering currents are mediated by inwardly rectifying potassium (Kir) channels which are expressed in astrocytes (Tanemoto et al, 2000; Hibino et al, 2004; Kofuji and Newman, 2004; Simard and Nedergaard, 2004; Butt and Kalsi, 2006). The most frequent mutation of KCNJ10 was R65P at the cytoplasmic end of transmembrane region (TM) and others include G77R (TM-1), C140R (extracellular loop between TM-1 and TM-2), T164I, A167V (cytoplasmic end of TM-2), R175Q, R199X, and R297C (C-terminal domain; Reichold et al, 2010; Sala-Rabanal et al, 2010; Tang et al, 2010) All these mutations caused drastic decreases in K+ currents mediated by Kir4.1 and Kir4.1/5.1 channels, suggesting that the impaired functioning of astrocytic Kir4.1 channels causes epileptic seizures by disrupting spatial K+ buffering. Expressional analysis revealed pathophysiological alterations in Kir4.1 expression in patients with TLE (Das et al, 2012; Heuser et al, 2012; Steinhäuser et al, 2012), Frontiers in Cellular Neuroscience www.frontiersin.org
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