title: Epigenetic reprogramming of cortical neurons through alteration of dopaminergic circuits.
abstract: 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.
authors.affiliation: 1] Department of Microbiology and Molecular Genetics and INSERM/UCI U904, University of California Irvine, Irvine, CA, USA [2] Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA, USA.
authors.forename: K
authors.identifier: 0000000230093821
authors.initials: K
authors.lastname: Brami-Cherrier
authors.affiliation: 1] Department of Microbiology and Molecular Genetics and INSERM/UCI U904, University of California Irvine, Irvine, CA, USA [2] Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Anzalone
authors.affiliation: 1] Department of Microbiology and Molecular Genetics and INSERM/UCI U904, University of California Irvine, Irvine, CA, USA [2] Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ramos
authors.affiliation: Munich Cluster for Systems Neurology (SyNergy) and Adolf-Butenandt Institute, Ludwig Maximilians University of Munich, Munich, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Forne
authors.affiliation: 1] Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA, USA [2] Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Macciardi
authors.affiliation: 1] Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA, USA [2] Munich Cluster for Systems Neurology (SyNergy) and Adolf-Butenandt Institute, Ludwig Maximilians University of Munich, Munich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Imhof
authors.affiliation: 1] Department of Microbiology and Molecular Genetics and INSERM/UCI U904, University of California Irvine, Irvine, CA, USA [2] Center for Epigenetics and Metabolism, University of California Irvine, Irvine, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Borrelli
mesh_terms: D000818:Animals; D017660:Autoreceptors / Q000235:genetics / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology*; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology*; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D015870:Gene Expression; D006657:Histones / Q000378:metabolism; D008822:Mice, Transgenic; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology*; D011618:Psychotic Disorders / Q000188:drug therapy / Q000503:physiopathology; D019257:Quinpirole / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
chemical_list: D017660:Autoreceptors; D018491:Dopamine Agonists; D006657:Histones; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D004298:Dopamine