MECP2 Knockout Cell Lysate

Developmental regression occurs in approximately one-third of children with autism spectrum disorder (ASD). There is a strong genetic influence in ASD and hundreds of genes have been implicated. Theories suggest that regressive ASD is a neurobiological subtype with potentially different causes. This review examines the evidence of genetic influences in regression and provides a summary of its frequency among ASD-associated single-gene disorders. The few twin- and family studies reporting on the concordance of regressive ASD among twin pairs and siblings provide mixed results, and no conclusions of the variance explained by either genetic or environmental factors can be drawn. Among the 89 genes robustly associated with ASD, 16 have been connected to regression, of which seven showed rates of regression higher than 30% among the mutation carriers. The molecular functions of these genes highlight important roles of transcriptional and synapse regulation for regression. Overall, this review shows our limited understanding of factors influencing regressive ASD and calls for additional studies to answer the open questions.

Inhibitors of DNA methylation and orexin type-1 receptor antagonists modulate the neurobiological effects driving drugs of abuse and natural reinforcers by activating common brain structures of the mesolimbic reward system. In this study, we applied a self-administration paradigm to assess the involvement of factors regulating DNA methylation processes and satiety or appetite signals. These factors include Dnmts and Tets, miR-212/132, orexins, and orx-R1 genes. The study focused on dopamine projection areas such as the prefrontal cortex (PFCx) and caudate putamen (CPu) and in the hypothalamus (HP) that is interconnected with the reward system. Striking changes were observed in response to both reinforcers, but differed depending on contingent and non-contingent delivery. Expression also differed in the PFCx and the CPu. Cocaine and food induced opposite effects on Dnmt3a expression in both brain structures, whereas they repressed both miRs to a different extent, without affecting their primary transcript in the CPu. Unexpectedly, orexin mRNAs were found in the CPu, suggesting a transport from their transcription site in the HP. The orexin receptor1 gene was found to be induced by cocaine in the PFCx, consistent with a regulation by DNA methylation. Global levels of 5-methylcytosines in the PFCx were not significantly altered by cocaine, suggesting that it is rather their distribution that contributes to long-lasting behaviors. Together, our data demonstrate that DNA methylation regulating factors are differentially altered by cocaine and food. At the molecular level, they support the idea that neural circuits activated by both reinforcers do not completely overlap.