Schizophrenia risk gene plays key role in early brain development

The results of a recent study show that schizophrenia may develop during early brain development.

Scientists have found that a gene linked to schizophrenia plays a critical role in brain development before birth, which supports the idea that the disorder arises from disruptions in early brain wiring, and that psychosis is a late stage of the condition.

The researchers, led by a team from Pennsylvania State University in State College, believe that their discovery may lead to better treatments for schizophrenia.

In a paper that has been published in the journal Molecular Psychiatry, they explain how they discovered molecular evidence that the gene may be involved in the development of schizophrenia and other psychiatric disorders.

The gene, called ZNF804A, influences the translation of genetic instructions into proteins and the growth and migration of nerve cells in the brain.

"A recent study identified over 100 genes associated with schizophrenia risk, but their functions are largely unknown," says lead author Yingwei Mao, an associate professor of biology at Pennsylvania State University. "We found that ZNF804A affects brain structure and function during early fetal development."

Schizophrenia begins in early brain

Schizophrenia is a severe chronic mental disorder that disrupts thinking, perception, language, emotions, and behavior.

The disorder, which affects around 1 percent of adults in the United States, gives rise to psychotic symptoms such as delusions and hallucinations that typically strike during late adolescence and early adulthood.

Although there is currently no cure for schizophrenia, there are treatments that can alleviate many of the disabling symptoms and help patients to lead an independent, productive life.

Some experts suggest that schizophrenia is a complex combination of different disorders that arise through interactions between genes and environment.

There have also been suggestions that the disease is linked to faulty wiring caused by problems in early development of the brain before birth.

For their study - in which they used cell cultures and mouse models - Prof. Mao and colleagues decided to focus on ZNF804A because it is a "top candidate gene" that has often been linked to schizophrenia. "However," they note, "its neural functions are largely unknown."

Influential impact on other genes

The team found that ZNF804A interacts with and alters the expression of several other genes, including some that have been linked with schizophrenia.

Nine of the genes that ZNF804A interacts with appear to regulate the translation of ribonucleic acid in making proteins.

Using mice, the team also showed that ZNF804A plays a critical role in two processes that feature in the early fetal development of the brain: the proliferation of neuronal stem cells, and the migration of nerve cells to particular places.

Neuronal stem cells are precursor cells that have the potential to specialize into different types of cell in the brain, including nerve cells, or neurons, which are the cells that receive, process, and send information.

The researchers found that when they suppressed ZFP804A expression, it decreased replication of neuronal stem cells "and migration of cortical neurons, suggesting that the proper expression of ZNF804A is critical for neural development, and that the disrupted expression may lead to disorders."

They conclude that their findings reveal a new role for ZFP804A and "provide new insight into the underlying molecular mechanisms of psychiatric disorders."

"Determining the role of ZNF804A is the first step in understanding how schizophrenia-associated genes contribute to abnormal brain development."

Prof. Yingwei Mao

"Understanding how these genes interact to contribute to the development of schizophrenia," adds Prof. Mao, "may allow us to identify the general pathway of the disease, potentially providing a better target for treatment."

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