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Schizophrenia gene discovery breakthrough

By Deborah Smith, Science Writer
July 9 2003

By creating a genetically modified mouse with schizophrenia, researchers led by the Nobel laureate Susumu Tonegawa have identified a gene in people linked to a high risk of developing the mental illness.

Professor Tonegawa said the discovery was likely to lead to a much needed new class of drugs for the disease - the first drugs designed to target its underlying genetic causes.

People could also be tested in future to see whether they were at increased risk of becoming ill before they developed symptoms.

Professor Tonegawa, of the Massachusetts Institute of Technology, is an expert in the brain and memory.

To study memory, he has developed a unique method for switching off a gene in just a tiny part of a mouse's brain.

One mouse created this way was found to have a poor working memory - the kind of memory we need to find reading glasses we have put down, or our way back to a car in the carpark.

People with schizophrenia usually have a poor working memory, which is also why their speech can be incoherent. "It's a very common impairment," Professor Tonegawa told the International Congress of Genetics in Melbourne yesterday.

His team realised the modified mice had other symptoms that were strikingly similar to the disease, such as social withdrawal. Mice like to cuddle up to each other when they sleep, "but the two mutants don't want to be together".

The modified mice also reacted in the same way as sick people on a test used to diagnose schizophrenia, in which their reaction to loud noises was monitored. Drugs used to treat affected people resulted in improvements in the mice, too. And the mice messed up their cage, scattering their nesting material about.

"This is the first knockout mouse to show such a comprehensive array of behavioural abnormalities that mirror the abnormal behaviour of human schizophrenia patients," Professor Tonegawa said.

The mice had been genetically modified in part of their forebrain so they did not make the chemical calcineurin.

When collaborators at Rockefeller University, New York, studied the DNA from families affected by schizophrenia they found those with the disease were more likely to have a defective version of a gene called PPP3CC that is associated with the production of calcineurin.

Professor Tonegawa said schizophrenia was a complex disease, with perhaps 20 to 30 genes contributing to the risk. But he believed many of them could influence the calcineurin chemical pathway in the brain.

The research appears in the Proceedings of the National Academy of Sciences. Professor Tonegawa was awarded his Nobel in 1987 for genetic discoveries about the immune system.




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