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The Effect of ASIC3 Knockout on Corticostriatal Circuit and Mouse Self-grooming Behavior

Wu, Wei-Li and Cheng, Sin-Jhong and Lin, Shing-Hong and Chuang, Yu-Chia and Huang, Eagle Yi-Kung and Chen, Chih-Cheng (2019) The Effect of ASIC3 Knockout on Corticostriatal Circuit and Mouse Self-grooming Behavior. Frontiers in Cellular Neuroscience, 13 . Art. No. 86. ISSN 1662-5102. doi:10.3389/fncel.2019.00086.

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Stereotypic and/or repetitive behavior is one of the major symptoms of autism spectrum disorder (ASD). Increase of self-grooming behavior is a behavioral phenotype commonly observed in the mouse models for ASD. Previously, we have shown that knockout of acid-sensing ion channel 3 (ASIC3) led to the increased self-grooming behavior in resident-intruder test. Given the facts that ASIC3 is mainly expressed in the peripheral dorsal root ganglion (DRG) and conditional knockout of ASIC3 in the proprioceptors induced proprioception deficits. We speculate a hypothesis that stereotypic phenotype related to ASD, pararalled with striatal dysfunction, might be caused by proprioception defect in the peripheral sensory neuron origin. Herein, we investigate in depth whether and how ASIC3 is involved in the regulation of self-grooming behavior. First, we observed that Asic3 null mutant mice exhibited increased self-grooming in social interaction during juvenile stage. Similarly, they displayed increased self-grooming behavior in a novel cage in the absence of cagemate. To further understand the mechanism by which ASIC3 affects grooming behavior, we analyzed neurochemical, neuropathological and electrophysiological features in the dorsal striatum of Asic3 null mutant mice. Knockout of Asic3 increased dopamine (DA) activity and phospho-ERK immunoreactivities in the dorsal striatum. Furthermore, we detected a lower paired-pulse ratio (PPR) and impaired long-term potentiation (LTP) in corticostriatal circuits in Asic3 null mutant mice as compared with wild-type (WT) littermates. Moreover, knockout of Asic3 altered the medial spiny neurons in the striatum with defects in presynaptic function and decrease of dendritic spines. Lastly, genetic ablation of Asic3 specifically in parvalbumin-positive (PV^+) cells resulted in the increase of self-grooming behavior in mice. These findings suggest knockout of Asic3 in the PV^+ neurons alters grooming behavior by co-opting corticostriatal circuits.

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Wu, Wei-Li0000-0003-2610-1881
Chen, Chih-Cheng0000-0003-4768-5660
Additional Information: © 2019 Wu, Cheng, Lin, Chuang, Huang and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Received: 19 September 2018; Accepted: 20 February 2019; Published: 12 March 2019. We thank the Neuroscience Core Facility at Neuroscience Program of Academia Sinica, Taiwan. We thank Dr. John N. Wood for providing transgenic lines Nav1.8-Cre, Dr. Cheng-Han Lee for coordinating experimental animals and advising gene expression study, and Dr. Pao-Luh Tao for providing HPLC-ECD equipment for DA measurement. W-LW acknowledges a conference travel fellowship supported by the Robert K.S. Lim and Shih-Chun Wang Memorial Scholarships and Awards. Author Contributions: W-LW conducted and analyzed behavior experiments, immunohistochemistry, HPLC analysis, Golgi staining and gene expression analysis. S-JC performed and analyzed results from all electrophysiology experiments. S-HL generated and verified Asic3 conditional knockout mice. Y-CC analyzed dendritic spines in Golgi stain and performed gene expression experiment. EY-KH assisted in DA activity measurement. W-LW and C-CC collected, integrated, and interpreted the results and wrote the manuscript. This work was supported by the Institute of Biomedical Sciences, Academia Sinica (to C-CC), Neuroscience Program of Academia Sinica (AS-CFII-108-106, to S-JC), National Science Council Taiwan (NSC 101-2917-I-564-039, to W-LW), and grants from the Ministry of Science and Technology, Taiwan (MOST107-2320-B-006-072-MY3 to W-LW; MOST105-2320-B-001-018-MY3, MOST108-2321-B-001-005, and MOST107-2319-B-001-002, to C-CC). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding AgencyGrant Number
Academia SinicaAS-CFII-108-106
National Science Council (Taipei)NSC 101-2917-I-564-039
Ministry of Science and Technology (Taipei)MOST107-2320-B-006-072-MY3
Ministry of Science and Technology (Taipei)MOST105-2320-B-001-018-MY3
Ministry of Science and Technology (Taipei)MOST108-2321-B-001-005
Ministry of Science and Technology (Taipei)MOST107-2319-B-001-002
Subject Keywords:ASIC3, self-grooming, corticostriatal circuit, parvalbumin, proprioception
Record Number:CaltechAUTHORS:20190328-165908444
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Official Citation:Wu W-L, Cheng S-J, Lin S-H, Chuang Y-C, Huang EY-K and Chen C-C (2019) The Effect of ASIC3 Knockout on Corticostriatal Circuit and Mouse Self-grooming Behavior. Front. Cell. Neurosci. 13:86. doi: 10.3389/fncel.2019.00086
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:94265
Deposited By: George Porter
Deposited On:29 Mar 2019 19:40
Last Modified:16 Nov 2021 17:04

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