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Glia. 2012 May;60(6):965-78. doi: 10.1002/glia.22328. Epub 2012 Mar 19.

Kir4.1 channels mediate a depolarization of hippocampal astrocytes under hyperammonemic conditions in situ.

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  • 1Institute of Neurobiology, Faculty of Mathematics and Natural Sciences, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, Düsseldorf, Germany.

Abstract

Increased ammonium (NH(4) (+) ) concentration in the brain is the prime candidate responsible for hepatic encephalopathy (HE), a serious neurological disorder caused by liver failure and characterized by disturbed glutamatergic neurotransmission and impaired glial function. We investigated the mechanisms of NH(4) (+) -induced depolarization of astrocytes in mouse hippocampal slices using whole-cell patch-clamp and potassium-selective microelectrodes. At postnatal days (P) 18-21, perfusion with 5 mM NH(4) (+) evoked a transient increase in the extracellular potassium concentration ([K(+) ](o) ) by about 1 mM. Astrocytes depolarized by on average 8 mV and then slowly repolarized to a plateau depolarization of 6 mV, which was maintained during NH(4) (+) perfusion. In voltage-clamped astrocytes, NH(4) (+) induced an inward current and a reduction in membrane resistance. Amplitudes of [K(+) ](o) transients and astrocyte depolarization/inward currents increased from P3-4 to P18-21. Perfusion with 100 μM Ba(2+) did not alter [K(+) ](o) transients but strongly reduced both astrocyte depolarization and inward currents. NH(4) (+) -induced depolarization and inward currents were also virtually absent in slices from Kir4.1 -/- mice, while [K(+) ](o) transients were unaltered. Blocking Na(+) /K(+) -ATPase with ouabain caused an immediate and complex increase in [K(+) ](o) . Taken together, our results are in agreement with the hypothesis that reduced uptake of K(+) by the Na(+) , K(+) -ATPase in the presence of NH(4) (+) disturbs the extracellular K(+) homeostasis. Furthermore, astrocytes depolarize in response to the increase in [K(+) ](o) and by influx of NH(4) (+) through Kir4.1 channels. The depolarization reduces the astrocytes' capacity for channel-mediated flux of K(+) and for uptake of glutamate and might hereby contribute to the pathology of HE.

Copyright © 2012 Wiley Periodicals, Inc.

PMID:
22431254
[PubMed - indexed for MEDLINE]
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