Mouse model could ID mental illness gene

A schizophrenic mouse model has led the way to identification of a gene potentially predisposing humans to the devastating human mental illness.

The mouse model, developed by researchers led by Nobel prize-winning immunologist turned neuroscientist Susumu Tonegawa at Massachusetts Institute of Technology, is lacking expression of the calcineurin (CN) gene, also known as protein phosphatase 2B, in the forebrain.

Tonegawa said that his involvement in schizophrenia research came about by accident, after the calcineurin knockout mouse was developed to look at working memory deficiency. Calcineurin is thought to function in the brain by affecting synaptic plasticity, changing the strength of neuronal connections.

But when the behavioural changes of the mice were investigated further, they showed several abnormalities that bore striking similarities to behavioural patterns in schizophrenics, including increased locomotor activity, decreased social interaction, and impairments in pre-pulse inhibition.

Recognising that a mouse model was not enough, however, Tonegawa teamed up with the Rockefeller University group led by Maria Karayiorgou to investigate genes involved in humans. Using 410 families with histories of schizophrenia, the researchers focused in on a gene on chromosome 8, PPP3CC, which turns out to be the catalytic subunit of calcineurin in humans. The gene was found in a region of chromosome 8 previously identified as possibly harbouring schizophrenia susceptibility genes.

Now the researchers have turned their attention to other genes in the calcineurin pathway, reasoning that alterations in different genes in the same pathway may contribute to the disease.

"We believe that all of the genes in the pathway could be contributing [to the disease]," Tonegawa says. "There are also environmental factors there but they are not well understood. This is a tremendous endeavour to understand this."

The discovery for the first time provides pharmaceutical companies with a biological target for drug discovery, as well as a basis for diagnostic tests to be developed. Tonegawa says that a partnership with a drug company is "cooking".

"What people are trying to do, the great hope we have, is that by being able to understand genetic components of these diseases we'll be able to develop compounds whose direct molecular target is known," he says.

The research is published this week in the Proceedings of the National Academy of Science.