Searching for the aetiology of a complex multifaceted disorder such as schizophrenia can be like searching for the proverbial needle in a haystack. Just where do you begin? Not only does the disorder present as a constellation of symptoms, including delusions, hallucinations, disorganized thoughts and emotional and motivational deficits, but the reported pathophysiology includes several brain regions, such as the hippocampus, thalamus, superior temporal gyrus and prefrontal cortex. Add to this evidence implicating genetic, environmental and developmental factors, and the fact that most patients have been treated with a range of neuroleptic drugs, and the problem can seem to be insurmountable.

A report in the October issue of Neuron provides an intriguing hint that help may be at hand in the form of microarrray gene-expression profiling. Karoly Mirnics and colleagues from David Lewis's and Pat Levitt's groups narrowed their search to one region of the brain, the dorsal prefrontal cortex. This area of the brain has been implicated in the cognitive disturbances associated with schizophrenia and has also been shown to have altered expression of gene products linked to neurotransmission and second messenger systems. Applying microarray technology to this disease, the authors took a three-step approach. First, they used high-density cDNA microarrays to compare the levels of over 7,000 gene transcripts in the prefrontal cortex of matched pairs of schizophrenic patients and controls. A data-mining technique revealed that transcripts encoding a specific set of proteins that regulate presynaptic function were decreased in all subjects with schizophrenia, with a different pattern across patients. The results for the most consistently altered genes were then verified using in situ hybridization in both the original tissue and a new cohort of patients. Two of the most commonly changed transcripts were N-ethylmaleimide sensitive factor and synapsin II. Although the changes were modest compared to those reported for cancer with this approach, the results do demonstrate a consistent abnormality in schizophrenic patients.

Even though this complex analysis will need to be mirrored in other brain areas and will need to be extended to a wider variety of gene transcripts that encode proteins that regulate for example, specific neurotransmitter systems, this approach should provide some much needed raw data. It seems equally likely that bioinformatics will be a vital tool in the search for the aetiology of such a complex disorder.