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.
Highlights
Autism spectrum disorder (ASD) is characterized by three core behavioral deficits which include symptoms such as impaired sociability, language problems, and restricted or repetitive behaviors
Since there are a multitude of animal models for ASD due to its heterogeneity, to screen out therapeutic potentials of candidates with specific animal model might have limited applicability [50]
We found that prenatal exposure of valproic acid (VPA), an animal model of ASD, caused up-regulation of AChE
Summary
Autism spectrum disorder (ASD) is characterized by three core behavioral deficits which include symptoms such as impaired sociability, language problems, and restricted or repetitive behaviors. To further strengthen the above implications, small scale clinical trials have been performed using acetylcholinesterase inhibitors (AChEIs) such as donepezil, rivastigmine, and galantamine to ASD patients [24,25,26,27] These drugs have shown to produce varying degrees of efficacy in language skill, communication, and hyperactivity. In many studies including ours, rodents such as rats and mice prenatally exposed to VPA showed autistic behaviors; i.e. decreased sociability, increased repetitive behavior, hyperactivity, increased epileptic potential to electric shock and so on [29,30,31] These animals were utilized as plausible animal models for ASD more often.
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