title: Subchronic treatment of donepezil rescues impaired social, hyperactive, and stereotypic behavior in valproic acid-induced animal model of autism.
abstract: Autism spectrum disorder (ASD) is a group of pervasive developmental disorders with core symptoms such as sociability deficit, language impairment, and repetitive/restricted behaviors. Although worldwide prevalence of ASD has been increased continuously, therapeutic agents to ameliorate the core symptoms especially social deficits, are very limited. In this study, we investigated therapeutic potential of donepezil for ASD using valproic acid-induced autistic animal model (VPA animal model). We found that prenatal exposure of valproic acid (VPA) induced dysregulation of cholinergic neuronal development, most notably the up-regulation of acetylcholinesterase (AChE) in the prefrontal cortex of affected rat and mouse offspring. Similarly, differentiating cortical neural progenitor cell in culture treated with VPA showed increased expression of AChE in vitro. Chromatin precipitation experiments revealed that acetylation of histone H3 bound to AChE promoter region was increased by VPA. In addition, other histone deacetyalse inhibitors (HDACIs) such as trichostatin A and sodium butyrate also increased the expression of AChE in differentiating neural progenitor cells suggesting the essential role of HDACIs in the regulation of AChE expression. For behavioral analysis, we injected PBS or donepezil (0.3 mg/kg) intraperitoneally to control and VPA mice once daily from postnatal day 14 all throughout the experiment. Subchronic treatment of donepezil improved sociability and prevented repetitive behavior and hyperactivity of VPA-treated mice offspring. Taken together, these results provide evidence that dysregulation of ACh system represented by the up-regulation of AChE may serve as an effective pharmacological therapeutic target against autistic behaviors in VPA animal model of ASD, which should be subjected for further investigation to verify the clinical relevance.
authors.affiliation: Department of Neuroscience, School of Medicine, Konkuk University, Seoul, Korea.
authors.forename: Ji-Woon
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, School of Medicine, Konkuk University, Seoul, Korea.
authors.forename: Hana
authors.initials: H
authors.lastname: Seung
authors.affiliation: Center for Neuroscience Research, Institute of Biomedical Science and Technology, Konkuk University, Seoul, Korea.
authors.forename: Kyung Ja
authors.initials: KJ
authors.lastname: Kwon
authors.affiliation: Department of Neuroscience, School of Medicine, Konkuk University, Seoul, Korea.
authors.forename: Mee Jung
authors.initials: MJ
authors.lastname: Ko
authors.affiliation: Department of Neuroscience, School of Medicine, Konkuk University, Seoul, Korea.
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Department of Neuroscience, School of Medicine, Konkuk University, Seoul, Korea.
authors.forename: Hyun Ah
authors.initials: HA
authors.lastname: Oh
authors.affiliation: Department of Neuroscience, School of Medicine, Konkuk University, Seoul, Korea.
authors.forename: Chang Soon
authors.initials: CS
authors.lastname: Choi
authors.affiliation: Department of Neuroscience, School of Medicine, Konkuk University, Seoul, Korea.
authors.forename: Ki Chan
authors.initials: KC
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, School of Medicine, Konkuk University, Seoul, Korea.
authors.forename: Edson Luck
authors.initials: EL
authors.lastname: Gonzales
authors.affiliation: Department of Neuroscience, School of Medicine, Konkuk University, Seoul, Korea.
authors.forename: Jueng Soo
authors.initials: JS
authors.lastname: You
authors.affiliation: Department of Neuroscience, School of Medicine, Konkuk University, Seoul, Korea.
authors.forename: Dong-Hee
authors.initials: DH
authors.lastname: Choi
authors.affiliation: Department of Neuroscience, School of Medicine, Konkuk University, Seoul, Korea.
authors.forename: Jongmin
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Neuroscience, School of Medicine, Konkuk University, Seoul, Korea.
authors.forename: Seol-Heui
authors.initials: SH
authors.lastname: Han
authors.affiliation: Department of Neuroscience, School of Medicine, Konkuk University, Seoul, Korea.
authors.forename: Sung Min
authors.initials: SM
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, College of Pharmacy, Sahmyook University, Seoul, Korea.
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Cheong
authors.affiliation: Department of Neuroscience, School of Medicine, Konkuk University, Seoul, Korea.
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Shin
authors.affiliation: Department of Neuropsychiatry, School of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Geon Ho
authors.initials: GH
authors.lastname: Bahn
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001321:Autistic Disorder / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D000077265:Donepezil; D005260:Female; D006657:Histones / Q000378:metabolism; D007150:Immunohistochemistry; D007189:Indans / Q000627:therapeutic use*; D008813:Mice, Inbred ICR; D010880:Piperidines / Q000627:therapeutic use*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013239:Stereotyped Behavior / Q000187:drug effects*; D014635:Valproic Acid / Q000633:toxicity*
chemical_list: D006657:Histones; D007189:Indans; D010880:Piperidines; D014635:Valproic Acid; D000077265:Donepezil; D000110:Acetylcholinesterase