title: Genetic mapping of ASIC4 and contrasting phenotype to ASIC1a in modulating innate fear and anxiety.
abstract: Although ASIC4 is a member of the acid-sensing ion channel (ASIC) family, we have limited knowledge of its expression and physiological function in vivo. To trace the expression of this ion channel, we generated the ASIC4-knockout/CreERT(2)-knockin (Asic4(Cre) (ERT) (2)) mouse line. After tamoxifen induction in the Asic4(Cre) (ERT)(2)::CAG-STOP(floxed)-Td-tomato double transgenic mice, we mapped the expression of ASIC4 at the cellular level in the central nervous system (CNS). ASIC4 was expressed in many brain regions, including the olfactory bulb, cerebral cortex, striatum, hippocampus, amygdala, thalamus, hypothalamus, brain stem, cerebellum, spinal cord and pituitary gland. Colocalisation studies further revealed that ASIC4 was expressed mainly in three types of cells in the CNS: (i) calretinin (CR)-positive and/or vasoactive intestine peptide (VIP)-positive interneurons; (ii) neural/glial antigen 2 (NG2)-positive glia, also known as oligodendrocyte precursor cells; and (iii) cerebellar granule cells. To probe the possible role of ASIC4, we hypothesised that ASIC4 could modulate the membrane expression of ASIC1a and thus ASIC1a signaling in vivo. We conducted behavioral phenotyping of Asic4(Cre) (ERT)(2) mice by screening many of the known behavioral phenotypes found in Asic1a knockouts and found ASIC4 not involved in shock-evoked fear learning and memory, seizure termination or psychostimulant-induced locomotion/rewarding effects. In contrast, ASIC4 might play an important role in modulating the innate fear response to predator odor and anxious state because ASIC4-mutant mice showed increased freezing response to 2,4,5-trimethylthiazoline and elevated anxiety-like behavior in both the open-field and elevated-plus maze. ASIC4 may modulate fear and anxiety by counteracting ASIC1a activity in the brain.
authors.affiliation: Graduate institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.|Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan.
authors.forename: Shing-Hong
authors.initials: SH
authors.lastname: Lin
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan.
authors.forename: Ya-Chih
authors.initials: YC
authors.lastname: Chien
authors.affiliation: Taiwan Mouse Clinic-National Comprehensive Mouse Phenotyping and Drug Testing Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Chiang
authors.affiliation: Taiwan Mouse Clinic-National Comprehensive Mouse Phenotyping and Drug Testing Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Yan-Zhen
authors.initials: YZ
authors.lastname: Liu
authors.affiliation: Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Cheng-Chang
authors.initials: CC
authors.lastname: Lien
authors.affiliation: Graduate institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.|Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan.|Taiwan Mouse Clinic-National Comprehensive Mouse Phenotyping and Drug Testing Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Chih-Cheng
authors.initials: CC
authors.lastname: Chen
mesh_terms: D062565:Acid Sensing Ion Channels / Q000235:genetics / Q000378:metabolism*; D000661:Amphetamine / Q000633:toxicity; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism*; D001823:Body Composition / Q000187:drug effects / Q000235:genetics; D004435:Eating / Q000187:drug effects / Q000235:genetics; D004965:Estrogen Antagonists / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D006948:Hyperkinesis / Q000139:chemically induced; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009420:Nervous System / Q000187:drug effects / Q000378:metabolism; D059225:Nociception / Q000187:drug effects / Q000502:physiology; D012640:Seizures / Q000139:chemically induced; D013629:Tamoxifen / Q000494:pharmacology; D013997:Time Factors
chemical_list: C568267:ASIC1 protein, mouse; C568270:ASIC4 protein, human; D062565:Acid Sensing Ion Channels; D004965:Estrogen Antagonists; D018690:Excitatory Amino Acid Agonists; D013629:Tamoxifen; D000661:Amphetamine; D007608:Kainic Acid
keywords: ASIC; Cre; behavioral phenotyping; interneuron; knockout mice