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Seizure termination by acidosis depends on ASIC1a

Nature Neuroscience volume 11, pages 816–822 (2008)Cite this article

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.

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Figure 1: ASIC1a reduces seizure severity.
Figure 2: ASIC1a disruption increases seizure duration and progression.
Figure 3: ASIC1a disruption reduces postictal depression.
Figure 4: ASIC1a mediates the antiepileptic effects of acid in hippocampal slices.
Figure 5: Inhibitory interneurons have prominent ASIC1a currents.
Figure 6: ASIC1a mediates the seizure-terminating effects of 10% CO2.

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Acknowledgements

We would like to thank J.M. Haenfler and A. Wunsch for excellent technical assistance, D.R. Langbehn and B. Zimmerman for assisting with statistical analysis, C.K. Kovach for assistance with EEG equipment and analysis, and F. Abboud and V. Snitsarev for assistance with EEG computational analysis. A.E.Z. was supported by the University of Iowa Interdisciplinary Training Program in Pain Research (US National Institute of Neurological Disorders and Stroke T32NS045549). M.J.W. is an Investigator of the Howard Hughes Medical Institute. J.A.W. was supported by US National Institute of Neurological Disorders and Stroke grant 1R21NS058309-01A1, a Veteran's Administration Advanced Career Development Award and a Research Initiatives grant from the University of Iowa Roy J. and Lucille A. Carver College of Medicine.

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Author notes

  1. Adam E Ziemann and Mikael K Schnizler: These authors contributed equally to this work.

Authors and Affiliations

  1. Medical Scientist Training Program, University of Iowa, Iowa City, 52242, Iowa, USA

    Adam E Ziemann & Michael J Welsh

  2. Departments of Molecular Physiology and Biophysics, University of Iowa, Iowa City, 52242, Iowa, USA

    Adam E Ziemann & Michael J Welsh

  3. Department of Internal Medicine, University of Iowa, Iowa City, 52242, Iowa, USA

    Mikael K Schnizler & Michael J Welsh

  4. Department of Neurosurgery, University of Iowa, Iowa City, 52242, Iowa, USA

    Gregory W Albert, Meryl A Severson & Matthew A Howard III

  5. Neuroscience Program, University of Iowa, Iowa City, 52242, Iowa, USA

    Matthew A Howard III, Michael J Welsh & John A Wemmie

  6. Howard Hughes Medical Institute, University of Iowa, Iowa City, 52242, Iowa, USA

    Michael J Welsh

  7. Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, 52242, Iowa, USA

    John A Wemmie

  8. Department of Veterans Affairs Medical Center, Iowa City, 52242, Iowa, USA

    John A Wemmie

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Contributions

A.E.Z. helped to generate the hypotheses for ASIC1a involvement in seizures, carried out the slice and in vivo electrophysiology/behavioral experiments, assessed seizure threshold, measured brain pH in response to seizures and CO2, assisted in studies using acutely dissociated neurons, wrote initial manuscript drafts and worked closely with other authors in editing the figures and manuscript. M.K.S. initiated, conceived, performed and interpreted electrophysiological experiments in dissociated neurons and assisted in preparation of the manuscript. M.A.S. helped to carry out and interpret the EEG experiments. G.W.A. assisted with seizure threshold studies. M.A.H. provided EEG equipment and helped with EEG interpretation. M.J.W. provided important overall direction and initiation for the project, contributed to experimental design and data interpretation, provided funding and wrote the manuscript. J.A.W. initiated development of the project, led experimental direction, interpreted data, carried out pilot experiments, provided funding and wrote the manuscript.

Corresponding authors

Correspondence to Michael J Welsh or John A Wemmie.

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Ziemann, A., Schnizler, M., Albert, G. et al. Seizure termination by acidosis depends on ASIC1a. Nat Neurosci 11, 816–822 (2008). https://doi.org/10.1038/nn.2132

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