Brain circuit problem likely sets stage for the 'voices' that are symptom of schizophrenia

St. Jude Children's Research Hospital scientists have identified problems in a connection between brain structures that may predispose individuals to hearing the "voices" that are a common symptom of schizophrenia. The work appears in the June 6 issue of the journal Science.

Researchers linked the problem to a gene deletion. This leads to changes in brain chemistry that reduce the flow of information between two brain structures involved in processing auditory information.

The research marks the first time that a specific circuit in the brain has been linked to the auditory hallucinations, delusions and other psychotic symptoms of schizophrenia. The disease is a chronic, devastating brain disorder that affects about 1 percent of Americans and causes them to struggle with a variety of problems, including thinking, learning and memory.

The disrupted circuit identified in this study solves the mystery of how current antipsychotic drugs ease symptoms and provides a new focus for efforts to develop medications that quiet "voices" but cause fewer side effects.

"We think that reducing the flow of information between these two brain structures that play a central role in processing auditory information sets the stage for stress or other factors to come along and trigger the 'voices' that are the most common psychotic symptom of schizophrenia," said the study's corresponding author Stanislav Zakharenko, M.D., Ph.D., an associate member of the St. Jude Department of Developmental Neurobiology. "These findings also integrate several competing models regarding changes in the brain that lead to this complex disorder."

The work was done in a mouse model of the human genetic disorder 22q11 deletion syndrome. The syndrome occurs when part of chromosome 22 is deleted and individuals are left with one rather than the usual two copies of about 25 genes. About 30 percent of individuals with the deletion syndrome develop schizophrenia, making it one of the strongest risk factors for the disorder. DNA is the blueprint for life. Human DNA is organized into 23 pairs of chromosomes that are found in nearly every cell.

Earlier work from Zakharenko's laboratory linked one of the lost genes, Dgcr8, to brain changes in mice with the deletion syndrome that affect a structure important for learning and memory. They found evidence that the same mechanism was at work in patients with schizophrenia. Dgcr8 carries instructions for making small molecules called microRNAs that help regulate production of different proteins.

For this study, researchers used state-of-the-art tools to link the loss of Dgcr8 to changes that affect a different brain structure, the auditory thalamus. For decades antipsychotic drugs have been known to work by binding to a protein named the D2 dopamine receptor (Drd2). The binding blocks activity of the chemical messenger dopamine. Until now, however, how that quieted the "voices" of schizophrenia was unclear.