Seeking schizophrenia genes

Japanese scientists have linked atypical expression patterns of the gene FABP7, which encodes the brain fatty acid binding protein 7, with human schizophrenia. Although initially attributed to environmental abnormalities, this debilitating disease is now accepted as being influenced by a strong, yet likely multifactorial, genetic component.

The phenotypic, or behavioral, outcomes of schizophrenia are perhaps just as complicated as the genotypic alterations underlying the disease. Fortunately, suppression of a particular startle response—known as prepulse inhibition (PPI)—provides an easily measurable biological readout of the sensory motor gating mechanisms that are often impaired in schizophrenia.

In an effort to identify genes associated with schizophrenia, a team led by Takeo Yoshikawa at the RIKEN Brain Science Institute in Wako, mapped genetic alterations associated with PPI in mice1.

After tracking the PPI responses of a panel of distinct inbred mouse strains for over one year, the researchers intercrossed the strains having the lowest and highest PPI scores. Next, the team scanned the genomes of the progeny for sets of microsatellite markers, or genetic ‘tags’, and compared the presence of these tags with the PPI scores.

Using progressively rigorous sets of tags, the researchers linked impaired PPI to a region of chromosome 10 containing approximately 30 genes. The team honed in on Fabp7 (Fig. 1), one gene within this region, because of its influence over the metabolism of the polyunsaturated fatty acid DHA (docosahexaenoic acid), a process often impaired in schizophrenia.

Encouragingly, although stronger in males than in females, human schizophrenia patients exhibit abnormally high expression of FABP7 similar to mice exhibiting defective PPI responses. Notably, mice rendered genetically deficient in Fabp7 also score low in PPI measurements and display stronger behavioral responses to chronic NMDA receptor antagonist treatment, another feature of schizophrenia.

Although the team detected defects in the maintenance of neural progenitor cells in Fabp7-deficient mice, future work is needed to elucidate the precise molecular mechanism through which alterations in Fabp7 expression promote schizophrenia-like behavior in mice and humans.

Similarly, why males seem to be more strongly affected by Fabp7 over-expression remains unclear. However, sex hormone-responsive elements in the DNA regions controlling Fabp7 expression might play a role.

“It is well known that malnutrition in utero increases the probability of future schizophrenia. Our results raise the importance of cohort studies to examine whether replenishment of DHA in pregnant mothers can be beneficial in reducing the chance of schizophrenia development in offspring,” says Yoshikawa.

Reference

1. Watanabe, A., Toyota, T., Owada, Y., Hayashi, T., Iwayama, Y., Matsumata, M., Ishitsuka, Y., Nakaya, A., Maekawa, M., Ohnishi, T., et al. Fabp7 maps to a quantitative trait locus for a schizophrenia endophenotype. PLoS Biology 5, 2469–2483 (2007).