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Received for publication January 10, 2006.
Revised May 2, 2006.
Accepted for publication May 2, 2006.
Once bound to methylated CpG sites, MeCP2 (methyl-CpG-binding protein 2) is thought to silence transcription of downstream genes by recruiting a histone deacetylase (HDAC). Mutations within the MeCP2 gene have been found to cause Rett syndrome, a disorder of arrested neuronal development. Using immunohistochemistry, we found that Mecp2, as well as the methyl-CpG-binding protein MBD1 were significantly induced in normal adult rat brain following repeated injections of fluoxetine or cocaine for ten days (1 injection/day). Mecp2 was not induced by repeated injections of GBR-12909 or nortriptyline. Together, the data indicate that the serotonergic system is predominantly involved. Using real time RT-PCR experiments, MBD1 mRNA and both Mecp2_e1 and Mecp2_e2 transcripts were found to be induced by fluoxetine. Induction of the methyl-binding proteins was accompanied with enhanced HDAC2 labeling intensity and mRNA synthesis in response to fluoxetine. Concomitantly, acetylated forms of histone H3 were found to be decreased. The effect was characterized in three serotonin projection areas, the caudate-putamen, the frontal cortex and the dentate gyrus subregion of hippocampus. Our data highlight GABAergic neurons as major target cells expressing Mecp2 in response to the serotonin-elevating agents and suggest that serotonin signaling enhances gene silencing in post-mitotic neurons.
Key words:
Serotonin, DNA binding sites, Immunocytochemistry, Regulation of gene expression, Anti-depressants, Cocaine
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