March 2016

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Researchers Find a Mechanism for Schizophrenia

Scientists uncovered a mechanism behind genetic variations previously linked to schizophrenia. The findings may lead to new clinical approaches.

Schizophrenia is a severe mental disorder that affects how a person thinks, feels, and behaves. It can cause hallucinations, delusions, and other mental problems, making the person seem to have lost touch with reality. The condition affects about 1 in 100 people.

Schizophrenia tends to run in families, so much research has focused on genetic variations that affect disease risk. Past studies have tied more than 100 genetic regions to schizophrenia risk. However, the specific genes and sequences that contribute to risk remained largely unknown.

To learn more, NIH-funded scientists examined the genetic region with the strongest link to schizophrenia risk. They noted associations near the C4 gene. This gene is needed to make a protein called C4, which plays a role in the immune systemThe cells and tissues that protect your body from invading viruses, bacteria, and other microscopic threats..

Human C4 exists in different forms. The researchers first developed a way to distinguish these. They found that one form in particular, C4A, was produced at high levels in the brains of schizophrenia patients. Further experiments showed that the C4 protein is found at sites called synapses, where nerve cells connect.

These findings, along with evidence from other studies, suggested that C4 might work to promote a process in the brain called synaptic pruning. In people, this occurs in the late teens to early adulthood—the same period when schizophrenia symptoms begin.

Experiments in mice showed that C4 tags synapses for pruning. The higher the levels of C4, the greater the synaptic pruning.

“Normally, pruning gets rid of excess connections we no longer need, streamlining our brain for optimal performance. But too much pruning can impair mental function,” says Dr. Thomas Lehner, an NIH expert in genomics and mental health. “Interventions that put the brakes on this pruning-process-gone-awry could prove transformative.”