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Schizophrenia Joins Reversible Neurodevelopmental Disorders


By Anette Breindl
Science Editor

Over the past few years, a shift has occurred in how researchers think of neurodevelopmental disorders. Such disorders were once considered immutable once the faulty wiring that was presumed to be at their heart was put in place during development.

But recent studies have shown that many such disorders can in fact be reversed, sometimes even at very late stages. (See BioWorld Today, April 12, 2012, and March 4, 2013.)

Now, researchers have added schizophrenia to the group of disorders that may be treatable in adulthood by targeting proteins that were long thought to have their influence during development. In animal studies, by changing the levels of the protein neuregulin in adults, they were able to affect symptoms of schizophrenia.

"Schizophrenia and many other mental illnesses have been considered neurodevelopmental disorders, where problems in wiring manifest as illness later on," senior author Lin Mei told BioWorld Today. But his team's studies, which appeared in the May 23, 2013, issue of Neuron, showed that "you can decrease neuregulin levels after neural development is considered complete, and symptoms will improve."

Deciding that a mouse is or isn't schizophrenic in any meaningful sense is, of course, its own challenge, as Mei pointed out.

"We are only talking about a mouse model," he said. "Many psychiatrists, myself included, do not believe that there are perfect mouse models of schizophrenia."

Still, he said, symptoms of schizophrenia fall into three broad categories – psychosis, social interaction deficits and cognitive deficits. In their paper, Mei and his team looked at both social interaction and cognition, and found that "both are impaired with high neuregulin, and can be treated by lowering levels" of the protein.

Mei and his team also looked at patterns of neural firing in response to certain types of stimulation, and found that they were altered in animals with high levels of neuregulin in ways that also mirror those seen in schizophrenic individuals.

Mei, who is at Georgia Regents University, and his team looked at neuregulin because it has been implicated as a schizophrenia risk factor gene in single-nucleotide polymorphism (SNP) studies.

Most of the SNPs that are correlated with schizophrenia risk, though, are not in protein-coding regions of the gene, which suggests that they may regulate its expression. Malfunctions related to neuregulin are thus likely to be due to the wrong amount of protein, rather than a version that can't function due to changes in its amino acid sequence.

In their studies, Mei and his team created inducible neuregulin knockouts and tested how overexpression of the protein would affect neural function and behavior in the animals. They found that high levels of neuregulin decreased the signaling of neurons that use glutamate and GABA as their transmitters, and that animals developed behavioral symptoms that are considered like those of schizophrenics.

When Mei and his team turned off the overexpression of neuregulin, to their surprise, the animals' symptoms improved.

Mei stressed that his team is not quibbling with the idea that neuregulin is important during brain development. But, he said, "abnormal behavior requires continued abnormal neuregulin expression in the adult."

How exactly mutations in neuregulin increase the risk for schizophrenia is not yet clear. Like neuregulin itself, its receptor – Erbb4 or Her4, which is well known to cancer researchers as a member of the family that also includes EGFR, Her2 and Her3 – has several SNPs that are associated with schizophrenia risk.

But in their work, Mei and his team found that it is neuregulin's signaling through another receptor, Lim kinase, that was critical for its effects.

Lin and his team plan to extend the studies by looking at the effects of turning neuregulin expression on and off in animals of different ages.

They also want to look at other components of the signaling network that neuregulin is part of. "Schizophrenia, like many other mental disorders, is polygenic – we want to tease out those interactions," Mei said.