Seizure termination by acidosis depends on ASIC1a.
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.
Adam E
AE
Ziemann
Mikael K
MK
Schnizler
Gregory W
GW
Albert
Meryl A
MA
Severson
Matthew A
MA
Howard
Michael J
MJ
Welsh
John A
JA
Wemmie
D062565:Acid Sensing Ion Channels; D000138:Acidosis / Q000139:chemically induced / Q000503:physiopathology*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D002245:Carbon Dioxide / Q000008:administration & dosage; D004569:Electroencephalography / Q000379:methods; D005260:Female; D006624:Hippocampus / Q000473:pathology; D006863:Hydrogen-Ion Concentration; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D007608:Kainic Acid; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D010433:Pentylenetetrazole; D010852:Picrotoxin; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D015222:Sodium Channels / Q000172:deficiency / Q000502:physiology*; D013997:Time Factors
D062565:Acid Sensing Ion Channels; D002245:Carbon Dioxide; D007608:Kainic Acid; D009419:Nerve Tissue Proteins; D010433:Pentylenetetrazole; D010852:Picrotoxin; D015222:Sodium Channels; C568267:ASIC1 protein, mouse