1. Kim JW, Seung H, Kwon KJ, Ko MJ, Lee EJ, Oh HA, Choi CS, Kim KC, Gonzales EL, You JS, Choi DH, Lee J, Han SH, Yang SM, Cheong JH, Shin CY, Bahn GH. {{Subchronic treatment of donepezil rescues impaired social, hyperactive, and stereotypic behavior in valproic Acid-induced animal model of autism}}. {PLoS One}. 2014; 9(8): e104927.
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.
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2. Pileggi LA, Malcolm-Smith S, Solms M. {{Investigating the role of social-affective attachment processes in cradling bias: The absence of cradling bias in children with Autism Spectrum Disorders}}. {Laterality}. 2014: 1-17.
Previous studies suggest that leftward cradling bias may facilitate mother-infant relationships, as it preferentially locates the infant in the mother’s left hemi-space, which is specialized for several social-affective processes. If leftward cradling bias is mediated by social-affective attachment processes, it should be reduced in humans who are deficient in such processes. Individuals diagnosed with Autism Spectrum Disorders (ASDs) constitute a population with known deficits in social and emotional relating. A pilot study confirmed reduced bias in this group, and in the present study, we elaborated methods to assess also the impact of higher cognitive processes on cradling bias. Direct systematic observation was used to investigate the occurrence of cradling bias in ASD, non-ASD intellectually disabled children and typically developing children. Ninety-three participants aged 5-15 years cradled a life-like doll on four separate occasions. Intelligence and executive functions were assessed. Regression analyses revealed that ASD diagnosis was the only significant predictor of atypical cradling preference. While intellectually disabled and typically developing children clearly preferred to cradle to the left, no preference was evident in the ASD group. Results support the hypothesis that leftward cradling bias is associated with basic social-affective capacities.
