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Updated: Sep 29, 2026
Modeling Neuronal Death and Degeneration in Mouse Primary Cerebellar Granule Neurons
Published on: November 6, 2017
Hypoxic depolarization of cerebellar granule neurons by specific inhibition of TASK-1
Leigh D Plant1, Paul J Kemp, Chris Peers
1School of Biomedical Sciences and Institute for Cardiovascular Research, University of Leeds, Leeds, UK.
Background And Purpose:
The mechanisms underlying neuronal excitotoxicity during hypoxic/ischemic episodes are not fully understood. One feature of such insults is a rapid and transient depolarization of central neurons. TASK-1, an open rectifying K+ leak channel, is significant in setting the resting membrane potential of rat cerebellar granule neurons by mediating a standing outward K+ current. In this study we investigate the theory that the transient neuronal depolarization seen during hypoxia is due to the inhibition of TASK-1.
Methods:
Activity of TASK-1 in primary cultures of rat cerebellar granule neurons was investigated by the whole-cell patch-clamp technique. Discriminating pharmacological and electrophysiological maneuvers were used to isolate the specific channel types underlying acute hypoxic depolarizations.
Results:
Exposure of cells to acute hypoxia resulted in a reversible and highly reproducible mean membrane depolarization of 14.2+/-2.6 mV (n=5; P<0.01). Two recognized means of inhibiting TASK-1 (decreasing extracellular pH to 6.4 or exposure to the TASK-1-selective inhibitor anandamide) abolished both the hypoxic depolarization and the hypoxic depression of a standing outward current, identifying TASK-1 as the channel mediating this effect.
Conclusions:
Our data provide compelling evidence that hypoxia depolarizes central neurons by specific inhibition of TASK-1. Since this hypoxic depolarization may be an early, contributory factor in the response of central neurons to hypoxic/ischemic episodes, TASK-1 may provide a potential therapeutic target in the treatment of stroke.
