Relationship between glial potassium regulation and axon excitability: A role for glial Kir4.1 channels

Uptake of K + released by axons during action potential propagation is a major function of astrocytes. Here, we demonstrate the importance of glial inward rectifying potassium channels (Kir) in regulating extracellular K + ([K + ] o ) and axonal electrical activity in CNS white matter of the mouse optic nerve. Increasing optic nerve stimulation frequency from 1 Hz to 10–35 Hz for 120 s resulted in a rise in [K + ] o and consequent decay in the compound action potential (CAP), a measure of reduced axonal activity. On cessation of high frequency stimulation, rapid K + clearance resulted in a poststimulus [K + ] o undershoot, followed by a slow recovery of [K + ] o and the CAP, which were more protracted with increasing stimulation frequency. Blockade of Kir (100 μM BaCl 2 ) slowed poststimulus recovery of [K + ] o and the CAP at all stimulation frequencies, indicating a primary function of glial Kir was redistributing K + to the extracellular space to offset active removal by Na + ‐K + pumps. At higher levels of axonal activity, Kir blockade also increased [K + ] o accumulation, exacerbating the decline in the CAP and impeding its subsequent recovery. In the Kir4.1−/− mouse, astrocytes displayed a marked reduction of inward currents and were severely depolarized, resulting in retarded [K + ] o regulation and reduced CAP. The results demonstrate the importance of glial Kir in K + spatial buffering and sustaining axonal activity in the optic nerve. Glial Kir have increasing importance in K + clearance at higher levels of axonal activity, helping to maintain the physiological [K + ] o ceiling and ensure the fidelity of signaling between the retina and brain. © 2012 Wiley Periodicals, Inc.