Altered expression of a single gene could prove to be the basis of even seemingly complex mental illnesses, according to microarray analyses of rat brains. These results may help explain the origins of schizophrenia in humans.

There is a consensus that schizophrenia, a severe and debilitating brain disorder characterized by hallucinations, delusions, paranoia, erratic thinking, and antisocial behavior, results from a combination of genetic and developmental conditions, but there has been no determination of the exact cause. Approximately 1% of the population develops schizophrenia during their lifetime and, although antipsychotic medications can relieve many of these symptoms, few people ever achieve a complete cure.

Now, a discovery in rats may help researchers pinpoint the molecular underpinnings of schizophrenia in humans. Gerard J.M. Martens of the Nijmegen Center for Molecular Life Sciences (Nijmegen, The Netherlands) studied rats that had been pharmacologically selected and bred to be either susceptible (APO-SUS) or resistant (APO-UNSUS) to the dopaminergic agonist apomorphine. Compared to their APO-UNSUS counterparts, APO-SUS rats display neuroanatomical, biochemical, and behavioral traits similar to those seen in humans with schizophrenia.

Martens's group performed microarray analyses on the hippocampus of APO-SUS and APO-UNSUS rats to look for variations in gene expression that might explain these phenotypic differences. Surprisingly, the only significant difference was in the expression of Aph-1b, a component of the γ-secretase enzyme complex that is involved in numerous neurodevelopmental signaling pathways, from neuronal migration, to angiogenesis, to tumor growth (Neuron, 17 February). Behavioral tests on rats grouped by their level of Aph-1b expression showed a gene dosage effect, that the authors attribute to a genomic rearrangement.

Whether these results apply to humans remains to be seen. As Martens tells Lab Animal, “Unlike rats [that have two copies], humans have only one Aph-1b gene, so a genomic rearrangement event resulting in a gene-dosage effect as observed in the rats seems unlikely to occur in humans. However, at the genetic or expression level there could well be a link between a γ-secretase component and complex disorders such as schizophrenia.” His team is currently analyzing the Aph-1b gene in humans and studying environmental factors that affect the gene's expression level in rats.