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

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. © 2012 Wiley Periodicals, Inc.