“Reprogramming” of Genes Causes Some Symptoms of Mental Illness—May Be Reversible

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Fabio Macciardi, M.D., Ph.D. - Brain and behavior research expert on schizophrenia
Fabio Macciardi, M.D., Ph.D.

In schizophrenia, the hallucinations and delusions that make up psychosis are presumed to be driven by an imbalance in dopamine, a chemical messenger in the brain. Antipsychotic medications quell these symptoms by blocking dopamine from activating one of its receptors, thus restoring balance to the system. But antipsychotics do not help much with the problems with motivation and thinking that also trouble many people with schizophrenia.

A new study with mice involving former NARSAD Independent Investigator Grantee, Fabio Macciardi, M.D., Ph.D., Professor of Psychiatry and Human Behavior at the University of California Irvine School of Medicine, offers a potential explanation for why antipsychotics fall short. Published online in Molecular Psychiatry on July 15th, the study finds that dopamine imbalance can also lead to a massive “reprogramming” of genes inside neurons. They also found that with the right targeted treatment, this reprogramming could be undone.

Led by Emiliana Borrelli at the University of California, Irvine, the study finds that mice genetically engineered to have a dopamine imbalance had nearly 2,000 genes that were “silenced” (were kept from being expressed in a typical manner). They found that neurons in the prefrontal cortex, a brain region involved in planning, decision making and other complex thought, were particularly affected. In contrast, neurons in the striatum, which also receive dopamine inputs, did not show such widespread silencing.

Treating these mice with the antipsychotic medication clozapine, which blocks dopamine receptors, did not do much to reverse the silencing of the genes. However, treating with a medication called quinpirole, which stimulates these dopamine receptors, did. The findings suggest that dopamine imbalance can effect different parts of the brain in different ways, requiring targeted treatments that have the potential to reverse or mediate the varied behavioral symptoms that result.

Read more from the Schizophrenia Research Forum.

Read the research paper abstract.

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