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.
|Titolo:||Epigenetic reprogramming of cortical neurons through alteration of dopaminergic circuits|
|Parole Chiave:||Animals; Autoreceptors; Corpus Striatum; Dopamine; Dopamine Agonists; Dopaminergic Neurons; Down-Regulation; Gene Expression; Histones; Mice, Transgenic; Prefrontal Cortex; Psychotic Disorders; Quinpirole; Receptors, Dopamine D2; Epigenesis, Genetic; Molecular Biology; Psychiatry and Mental Health; Cellular and Molecular Neuroscience|
|Settore Scientifico Disciplinare:||Settore MED/03 - Genetica Medica|
|Data di pubblicazione:||2014|
|Digital Object Identifier (DOI):||10.1038/mp.2014.67|
|Appare nelle tipologie:||01 - Articolo su periodico|