title: Expressing acid-sensing ion channel 3 in the brain alters acid-evoked currents and impairs fear conditioning.
abstract: Previous studies on mice with a disruption of the gene encoding acid-sensing ion channel 1a (ASIC1a) suggest that ASIC1a is required for normal fear behavior. To investigate the effects of altering the subunit composition of brain ASICs on behavior, we developed transgenic mice expressing ASIC3 via the pan-neuronal synapsin I promoter. These mice express ASIC3 in the brain, where the endogenous ASIC3 protein is not detected. We found that in ASIC3 transgenic mice, ASIC3 co-immunoprecipitated with the endogenous ASIC1a protein and distributed in the same subcellular brain fractions as ASIC1a. In addition, ASIC3 significantly increased the rate of desensitization of acid-evoked currents in cultured cortical neurons. Importantly, ASIC3 reduced Pavlovian fear conditioning to both context and auditory cues. These observations suggest that ASIC3 can heteromultimerize with ASIC1a in the brain and alter the biophysical properties of the endogenous channel complex. Moreover, these data suggest that ASIC subunit composition and channel desensitization may be critical determinants for ASIC-dependent behavior.
authors.affiliation: Interdisciplinary Graduate Program in Neuroscience, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: V C
authors.initials: VC
authors.lastname: Vralsted
authors.forename: M P
authors.initials: MP
authors.lastname: Price
authors.forename: J
authors.initials: J
authors.lastname: Du
authors.forename: M
authors.initials: M
authors.lastname: Schnizler
authors.forename: A M
authors.initials: AM
authors.lastname: Wunsch
authors.forename: A E
authors.initials: AE
authors.lastname: Ziemann
authors.forename: M J
authors.initials: MJ
authors.lastname: Welsh
authors.forename: J A
authors.initials: JA
authors.lastname: Wemmie
mesh_terms: D062565:Acid Sensing Ion Channels; D000143:Acids / Q000494:pharmacology; D000161:Acoustic Stimulation; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D003213:Conditioning, Psychological / Q000502:physiology*; D003463:Cues; D004594:Electrophysiology; D005239:Fear / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: C508378:ASIC3 protein, mouse; D062565:Acid Sensing Ion Channels; D000143:Acids; D015222:Sodium Channels