Dysfunction in dopamine signaling greatly changes the activity level of about 2,000 genes in the brain’s prefrontal cortex and may be an underlying cause of certain complex neuropsychiatric disorders such as schizophrenia, according to researchers at the University of California-Irvine (UCI).
This epigenetic alteration of gene activity in brain cells that receive this neurotransmitter showed for the first time that dopamine deficiencies can affect a variety of behavioral and physiological functions regulated in the prefrontal cortex. The study (“Epigenetic reprogramming of cortical neurons through alteration of dopaminergic circuits”), led by Emiliana Borrelli, Ph.D., a UCI professor of microbiology & molecular genetics, appears in Molecular Psychiatry.
“Our work presents new leads to understanding neuropsychiatric disorders,” Dr. Borrelli said. “Genes previously linked to schizophrenia seem to be dependent on the controlled release of dopamine at specific locations in the brain. Interestingly, this study shows that altered dopamine levels can modify gene activity through epigenetic mechanisms despite the absence of genetic mutations of the DNA.”
Dr. Borrelli and her team wanted to understand what would happen if dopamine signaling was hindered. To do this, they used mice that lacked dopamine receptors in midbrain neurons, which radically affected regulated dopamine synthesis and release. The researchers discovered that this receptor mutation profoundly altered gene expression in neurons receiving dopamine at distal sites in the brain, specifically in the prefrontal cortex. Dr. Borrelli said they observed a remarkable decrease in expression levels of some 2,000 genes in this area, coupled with a widespread increase in modifications of histones, particularly those associated with reduced gene activity.
“We observed a remarkable down regulation of gene expression in this area of ~2,000 genes, which involves a widespread increase in the histone repressive mark H3K9me2/3,” wrote the investigators. “This reprogramming process is coupled to psychotic-like behaviors in the mutant mice. Importantly, chronic treatment with a DA [dopamine] 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.”
Dr. Borrelli further noted that the dopamine receptor-induced reprogramming led to psychotic-like behaviors in the mutant mice and that prolonged treatment with a dopamine activator restored regular signaling, pointing to one possible therapeutic approach. He added that his research team is continuing its work to gain more insights into the genes altered by this dysfunctional dopamine signaling.