Article abstract
Nature Neuroscience 11, 816 - 822 (2008)
Published online: 8 June 2008 | doi:10.1038/nn.2132
Seizure termination by acidosis depends on ASIC1a
Adam E Ziemann1,2,9, Mikael K Schnizler3,9, Gregory W Albert4, Meryl A Severson4, Matthew A Howard III4,5, Michael J Welsh1,2,3,5,6 & John A Wemmie5,7,8
Abstract
Most seizures stop spontaneously; however, the molecular mechanisms that terminate seizures remain unknown. Observations that seizures reduced brain pH and that acidosis inhibited seizures indicate that acidosis halts epileptic activity. Because acid-sensing ion channel 1a (ASIC1a) is exquisitely sensitive to extracellular pH and regulates neuron excitability, we hypothesized that acidosis might activate ASIC1a, which would terminate seizures. Disrupting mouse ASIC1a increased the severity of chemoconvulsant-induced seizures, whereas overexpressing ASIC1a had the opposite effect. ASIC1a did not affect seizure threshold or onset, but shortened seizure duration and prevented seizure progression. CO2 inhalation, long known to lower brain pH and inhibit seizures, required ASIC1a to interrupt tonic-clonic seizures. Acidosis activated inhibitory interneurons through ASIC1a, suggesting that ASIC1a might limit seizures by increasing inhibitory tone. Our results identify ASIC1a as an important element in seizure termination when brain pH falls and suggest both a molecular mechanism for how the brain stops seizures and new therapeutic strategies.
- Medical Scientist Training Program, University of Iowa, Iowa City, Iowa 52242, USA.
- Departments of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242, USA.
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
- Department of Neurosurgery, University of Iowa, Iowa City, Iowa 52242, USA.
- Neuroscience Program, University of Iowa, Iowa City, Iowa 52242, USA.
- Howard Hughes Medical Institute, University of Iowa, Iowa City, Iowa 52242, USA.
- Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
- Department of Veterans Affairs Medical Center, Iowa City, Iowa 52242, USA.
- These authors contributed equally to this work.
Correspondence to: Michael J Welsh1,2,3,5,6 e-mail: michael-welsh@uiowa.edu
Correspondence to: John A Wemmie5,7,8 e-mail: john-wemmie@uiowa.edu
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