Seeking the Roots of Schizophrenia

Professor Claes Wahlestedt

The workings of the human brain — and the ways in which these workings can fail — are in many ways still a great mystery to scientists. This gap in knowledge is particularly devastating for patients suffering from schizophrenia.

But two studies recently published by Scripps Research investigators are helping to close that gap.

A recent study by Scripps Florida Professor Claes Wahlestedt for the first time linked specific microRNA to behavior problems associated with psychiatric disorders such as schizophrenia.

Scientists had previously known that a number of brain disorders — including schizophrenia, autism, and mood disorders — can involve a disruption in a particular signaling process in the brain called NMDA signaling. But the specific molecular components of the disruption remained a mystery.

Wahlestedt's team, however, discovered that the NMDA signaling disruption was associated with a reduction of a non-coding microRNA known as miR-219. Non-coding RNAs are small molecules that do not produce proteins, yet often play a vital role in gene expression.

"In the study we asked the question, 'Which non-coding RNA players might have something to do with NMDA signaling in the prefrontal cortex part of the brain?'" said Wahlestedt. "As we discovered, miRNA-219, which is a brain-specific microRNA, plays an integral part in the NMDA signaling process. Our findings strongly support the idea that this previously uncharacterized microRNA significantly modulates NMDA signaling and associated behavioral problems."

Wahlestedt's findings suggest that microRNA-219 could make a good drug target.

While Wahlestedt and his team were investigating the role of microRNA in schizophrenia's behavioral problems, Professor Ulrich Mueller and his team were perfecting a mouse model that could provide a great benefit to future researchers.

Mueller's team found that disrupting the function of a key molecule in the brain leads to microscopic brain abnormalities and schizophrenia-like behavior in mice.

"We found several microscopic pathologies and behavioral traits that are hallmarks of schizophrenia," said Mueller. "These findings in mice may help shed light on how schizophrenia, an often severe and debilitating disease, emerges in humans."

While the precise causes of schizophrenia are not entirely understood, the scientific consensus is that the disease results from a combination of genes and other factors. Schizophrenia runs in families, which is strong evidence that inherited genes play a role, but the disease is not completely genetic. In some cases, one identical twin will be struck with schizophrenia while the other one is not. This suggests that more than just genes are involved, and development is also suspected to be a factor.

In its paper, Mueller's team looked specifically at what happens when models lost the function of a brain protein called neuregulin — an important developmental protein that helps the brain form its distinct structures in early development and that has been linked to schizophrenia and numerous other mental health problems.

Mueller's team found that when models were deprived of neuregulin, the brain structures that allow one neuron to contact another began to form but did not mature completely. Instead, they fell apart. The effect was evident in behavioral tests, where models displayed hallmarks of schizophrenia such as social interaction problems and reduced anxiety.

These findings provide important new information for current hypotheses about the roots of schizophrenia, and offer a critical new route of inquiry.

Wahlestedt and Mueller's work represents vital new hope for the millions of Americans who suffer from schizophrenia, and demonstrates the many angles by which Scripps Research scientists approach diseases. Your support can help ensure that the most critical medical problems continue to receive a multi-pronged attack.