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Epigenetic reprogramming of cortical neurons through alteration of dopaminergic circuits


Alterations of the dopaminergic system are associated with the cognitive and functional dysfunctions that characterize complex neuropsychiatric disorders. We modeled a dysfunctional dopaminergic system using mice with targeted ablation of dopamine (DA) D2 autoreceptors in mesencephalic dopaminergic neurons. Loss of D2 autoreceptors abolishes D2-mediated control of DA synthesis and release. Here, we show that this mutation leads to a profound alteration of the genomic landscape of neurons receiving dopaminergic afferents at distal sites, specifically in the prefrontal cortex. Indeed, we observed a remarkable downregulation of gene expression in this area of ~2000 genes, which involves a widespread increase in the histone repressive mark H3K9me2/3. This reprogramming process is coupled to psychotic-like behaviors in the mutant mice. Importantly, chronic treatment with a DA agonist can revert the genomic phenotype. Thus, cortical neurons undergo a profound epigenetic reprogramming in response to dysfunctional D2 autoreceptor signaling leading to altered DA levels, a process that may underlie a number of neuropsychiatric disorders.

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We thank Drs F Torri and C De Mei for assistance and interest in the initial phase of this study; Dr P Sassone-Corsi for critical discussions and reading of the manuscript. This work was supported by NIH Grant DA024689 and INSERM-44790 (to EB).

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Correspondence to E Borrelli.

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Brami-Cherrier, K., Anzalone, A., Ramos, M. et al. Epigenetic reprogramming of cortical neurons through alteration of dopaminergic circuits. Mol Psychiatry 19, 1193–1200 (2014).

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