The findings, published in the journal Nature Communications, may give researchers a fresh path forward for developing more effective treatments and biomarker-based screening strategies.
More than 100 million people worldwide have either schizophrenia or bipolar disorder, which are characterized by periods of hallucinations, delusions and irregular thought processes. They are both linked to an overproduction of the neurotransmitter dopamine, a key regulator of reward-seeking behavior, emotional responses, learning and movement, among other functions.
“We’ve known since the 1970s that the effectiveness of antipsychotic medications is directly related to their ability to block dopamine signaling. However, the exact mechanism that sparks excessive dopamine in the brain and that leads to psychotic symptoms has been unclear,” said Viviane Labrie, PhD, assistant professor at Van Andel Research Institute (VARI) and corresponding author of the study.
“We now have a biological explanation that could help make a real difference for people with these disorders.”
The research team discovered a cluster of epigenetic marks that pumps up dopamine production while simultaneously scrambling the brain’s synapses, the information hubs that transmit rapid-fire neural messages responsible for healthy function. The result is a catastrophic shake-up of the brain’s organization and chemical balance that fuels symptoms of psychosis.
“What we’re seeing is a one-two punch — the brain is being flooded with too much dopamine and at the same time it is losing these critical neural connections,” Labrie said.
“Like many other neurological disorders, schizophrenia and bipolar disorder often have early, or prodromal, phases that begin years before obvious symptoms. It is our hope that our findings may lead to new biomarkers to screen for risk, which would then allow for earlier intervention.”
For the study, the researchers analyzed DNA derived from brain cells of individuals with either schizophrenia or bipolar disorder and compared them to healthy controls. Their analyses revealed a cluster of epigenetic marks in an enhancer at a gene called IGF2, a critical regulator of synaptic development.
Enhancers are stretches of DNA that help activate genes and can be major players in the development of diseases in the brain and other tissues.
This enhancer also controls the activity of a nearby gene called tyrosine hydroxylase, which produces an enzyme that keeps dopamine in check. When the enhancer is epigenetically switched on, production of dopamine becomes dysregulated, resulting in too much of the chemical in the brain.
Any molecular changes at this site may explain why psychosis brought on by dopamine frequently is accompanied by a disruption of brain synapses, a devastating double-hit that promotes symptoms.
The study controlled for genetic factors, sex, ethnicity, treatment history and lifestyle influences such as smoking, and the results were validated in experimental models of the disease.
“We used cutting-edge computational strategies to understand the events occurring in brain cells that underlie psychiatric disorders,” said Shraddha Pai, PhD, a postdoctoral fellow at University of Toronto and the study’s first author. “Our results were strengthened by additional studies in disease models. This comprehensive approach lends weight to our findings, which we believe will propel additional groundbreaking investigations into this enhancer at the IGF2 gene.”
Source: Van Andel Research Institute