Subject(s)
Autoreceptors/metabolism , Dopaminergic Neurons/physiology , Prefrontal Cortex/physiopathology , Receptors, Dopamine D2/metabolism , Animals , Autoreceptors/genetics , Behavior, Animal/physiology , Chromatin/metabolism , DNA-Binding Proteins , Epigenesis, Genetic , Gene Expression , Histones/metabolism , Methylation , Mice, Knockout , Nerve Tissue Proteins/metabolism , Nuclear Proteins/metabolism , Receptors, Dopamine D2/geneticsABSTRACT
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.
Subject(s)
Autoreceptors/metabolism , Corpus Striatum/physiopathology , Dopaminergic Neurons/physiology , Epigenesis, Genetic , Prefrontal Cortex/physiopathology , Receptors, Dopamine D2/metabolism , Animals , Autoreceptors/genetics , Corpus Striatum/drug effects , Dopamine/metabolism , Dopamine Agonists/pharmacology , Dopaminergic Neurons/drug effects , Down-Regulation , Gene Expression , Histones/metabolism , Mice, Transgenic , Prefrontal Cortex/drug effects , Psychotic Disorders/drug therapy , Psychotic Disorders/physiopathology , Quinpirole/pharmacology , Receptors, Dopamine D2/agonists , Receptors, Dopamine D2/geneticsABSTRACT
OBJECTIVE: To study the longitudinal dynamics of anti-myelin oligodendrocyte glycoprotein (MOG) autoantibodies in childhood demyelinating diseases. METHODS: We addressed the kinetics of anti-MOG immunoglobulins in a prospective study comprising 77 pediatric patients. This was supplemented by a cross-sectional study analyzing 126 pediatric patients with acute demyelination and 62 adult patients with multiple sclerosis (MS). MOG-transfected cells were used for detection of antibodies by flow cytometry. RESULTS: Twenty-five children who were anti-MOG immunoglobulin (Ig) positive at disease onset were followed for up to 5 years. Anti-MOG antibodies rapidly and continuously declined in all 16 monophasic patients with acute disseminated encephalomyelitis and in one patient with clinically isolated syndrome. In contrast, in 6 of 8 patients (75%) eventually diagnosed with childhood MS, the antibodies to MOG persisted with fluctuations showing a second increase during an observation period of up to 5 years. Antibodies to MOG were mainly IgG 1 and their binding was largely blocked by pathogenic anti-MOG antibodies derived from a spontaneous animal model of autoimmune encephalitis. The cross-sectional part of our study elaborated that anti-MOG Ig was present in about 25% of children with acute demyelination, but in none of the pediatric or adult controls. Sera from 4/62 (6%) adult patients with MS had anti-MOG IgG at low levels. CONCLUSIONS: The persistence or disappearance of antibodies to MOG may have prognostic relevance for acute childhood demyelination.
