MHRI research identifies targets for psychiatric disease

High-throughput screening techniques are being used in a unique approach to studying the molecular causes of schizophrenia and bipolar disorder.

Speaking at the Australian Health and Medical Research Congress (AHMRC) yesterday, Prof Brian Dean of the Mental Health Research Institute in Melbourne said that genomics and proteomics techniques were being applied to identify genes and proteins involved in the two psychiatric diseases.

Concentrating on specific regions in the prefrontal cortex, as well as the hippocampus and the thalamus, the researchers have analysed messenger RNA from post-mortem brain tissue using random fragment differential display.

From a survey of around 12,000 genes, Dean said that 153 were differentially displayed in comparison to brains from control subjects, with about a third of the genes expressed at increased levels.

Comparisons between expression in brains from schizophrenics still in the early clinical phase of the disorder, and those in the later stages of the disorder, as well as with brains from bipolar individuals and controls were also performed.

In addition, two-dimensional gels were used to examine the proteins in brain tissue, again identifying a small number of genes that had increased or decreased expression in brains from schizophrenic patients.

The majority of the genes identified have been known genes, and fall into several major categories, including genes involved in metabolism, signal transduction, transcription and proteolysis, as well as neurotransmitter receptor and ion channel genes. But Dean believes that two groups of genes might be important in the development of schizophrenia, those involved in neurodevelopment and structural integrity of the brain.

"There is evidence in schizophrenia that subtle changes might occur early in an individual's life. It's not obvious at first but in hindsight you can see abnormal behaviour," he said. "If structural proteins are affected by schizophrenia, then that affects the whole dynamics of the brain, its physical stability."

Dean said the next step would be to take five to 10 genes that were likely to be critical in schizophrenia and bipolar disorder, and fully characterise their functions.

Ultimately, he would like to be able to look at the genes and proteins in the serum of living patients. While the quality of the brains used in the study is rigorously controlled, it can be up to five hours after death by the time they are frozen, and this limits the amount of information that can be obtained.

Dean's team also spends as much as six months on a comprehensive case history of each individual whose brain they plan to use, to ensure that the diagnosis of schizophrenia or bipolar illness is correct.

"On average we reject nine out of 10 opportunities to collect. We probably get about 12 a year," Dean said.

Dean's approach to investigating the molecular causes of psychiatric disorders is in some ways the opposite of the more traditional genetic approach, which uses families to slowly tease out the genes involved in complex genetic disorders. Complicating the research is the probability that schizophrenia is a syndrome with several genetic causes, rather than a single discrete disease.

While there is evidence that schizophrenia is inherited, other non-genetic factors also play a big part in the development of the disease. When one identical twin has schizophrenia, the other twin will only develop the illness 48 per cent of the time.

Dean said that purely genetic approaches have not provided enough information on psychiatric disorders to date, because of the complexity of the diseases. But he sees the two approaches as being very complementary.

"We'll have a dynamic relationship -- genes discovered through high-throughput screening will become target genes for geneticists, and genes they discover will be looked at by genomics and proteomics," he said. "It's an exciting time for us. We've taken on the most complex challenge available in biological science -- psychiatric illness."