During his PhD, Steven McCarroll was surprised to receive a phone call from an old classmate – and startled to find the call came from prison. His friend had been walking down the street when he was gripped by the conviction that people were chasing him, and broke into an apartment to hide.

McCarroll’s friend was in the throes of schizophrenia. Symptoms of the condition include hallucinations, such as hearing voices, and paranoid delusions.

The event set the stage for McCarroll’s career. Now a molecular biologist at Harvard Medical School in Boston, his latest work offers tantalising clues about the cause of the condition, which is poorly understood and can affect people for life. It suggests that schizophrenia can result from a normal stage of teenage brain maturation gone wrong.

“It’s really exciting because it could lead to new ways of treating the disorder,” says Oliver Howes, who studies psychosis at King’s College London.

The work builds on a recent landmark study that pointed to 108 regions of our DNA in which certain variants raise the risk of schizophrenia. The most strongly implicated area is a large region of the genome that encodes proteins involved in the immune system – on the face of it, a puzzling find for a brain disorder.

Risky component

McCarroll’s team has now found that people with the risky variants of this region have higher levels of a molecule called complement component 4. In the blood, C4 binds to microbes to signal that they should be eaten by immune cells.

By genetically engineering mice that lack C4, the team showed it has a second role – in the brain. Here, C4 binds to neurons at the points where they connect with other neurons, and signals that these connections, or synapses, should also be engulfed by immune cells. “It targets things for swallowing,” says McCarroll.

As teenagers’ brains mature, they go through a developmental stage called pruning, in which they lose synapses. Post-mortem studies show that people with schizophrenia have fewer synapses. McCarroll speculates that the risky C4 gene variants cause too much pruning. “It would make a lot of sense,” he says.

We’ve known that the immune system plays a role in schizophrenia for a while – and this could be the link, saysSteven Hyman, director of the Stanley Center for Psychiatric Research in Cambridge, Massachusetts, and former head of the US National Institute of Mental Health. For this reason, he describes the work as one of the most important findings in schizophrenia that he can remember.

No single cause

This one theory is unlikely to account for all cases, because schizophrenia is such a variable condition, says Robin Murray of King’s College London. But it may explain why, for some people, the first signs appear in adolescence, when pruning peaks.

These initial symptoms include problems with memory and attention, emotional withdrawal and a lack of motivation, which McCarroll’s classmate also experienced, and meant he dropped out of his PhD. Such features receive much less attention than psychotic symptoms, but tend to precede psychosis by a few years. Unlike psychosis, there are no drugs to alleviate them.

McCarroll thinks that a lack of synapses may be key to explaining these less-known aspects of schizophrenia. If so, his work offers a way to tackle them. For example, drugs that work against a molecule related to C4 are already being tested for the eye disease age-related macular degeneration.

“People make the mistake of equating schizophrenia with psychosis,” McCarroll says. “If you ask patients what are the hardest things to endure, [many] would say the fact they can no longer hold down a job.”



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