Cocaine represses protein phosphatase-1Cβ through DNA methylation and Methyl-CpG Binding Protein-2 recruitment in adult rat brain

• Published in: Neuropharmacology 2013-10, Vol.73, p.31-40
• Main Authors: Pol Bodetto, Sarah, Carouge, Delphine, Fonteneau, Mathieu, Dietrich, Jean-Bernard, Zwiller, Jean, Anglard, Patrick
• Format: Article
• Language: English
• Subjects: Animals; Brain - drug effects; Brain - metabolism; Caudate Nucleus - drug effects; Caudate Nucleus - metabolism; Cocaine; Cocaine - pharmacology; DNA (Cytosine-5-)-Methyltransferases - biosynthesis; DNA methylation; DNA Methylation - drug effects; DNA-Binding Proteins - drug effects; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Drugs of abuse; Epigenetics; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Life Sciences; Male; MeCP2; Mutation; Neurobiology; Neurons and Cognition; Protein Phosphatase 1 - biosynthesis; Protein phosphatase-1; Protein Subunits - biosynthesis; Putamen - drug effects; Putamen - metabolism; Rats; Rett syndrome
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2013.05.005

Repeated cocaine exposure induces epigenetic factors such as DNA methyl-binding proteins, indicating that resulting changes in gene expression are mediated by alterations in brain DNA methylation. While the activity of protein phosphatase type-1 (PP1) is involved in cocaine effects and in brain plasticity, the expression of the PP1Cβ catalytic subunit gene was identified here as modulated by cocaine. Its expression was induced together with that of PP1Cγ in the brain of Methyl-CpG Binding Protein-2 (Mecp2) mutant mice, whereas PP1Cα expression was not affected, illustrating a different regulation of PP1C isoforms. Repeated cocaine administration was found to increase DNA methylation at the PP1Cβ gene together with its binding to Mecp2 in rat caudate putamen, establishing a link between two genes involved in cocaine-related effects and in learning and memory processes. Cocaine also increased DNMT3 expression, resulting in PP1Cβ repression that did not occur in the presence of DNMT inhibitor. Cocaine-induced PP1Cβ repression was observed in several brain structures, as evaluated by RT-qPCR, immunohistochemistry and Western blot, but did not occur after a single cocaine injection. Our data demonstrate that PP1Cβ is a direct MeCP2-target gene in vivo. They suggest that its repression may participate to behavioral adaptations triggered by the drug. •Cocaine represses protein phosphatase-1Cβ in rat brain structures.•Cocaine increases DNMT levels, DNA methylation and the recruitment of Mecp2 at the PP1Cβ gene.•PP1Cβ and γ levels are induced in Mecp2 mutant mice and likely contribute to their cognitive deficits.•PP1C isoforms are differentially regulated by Mecp2 and cocaine.