Genes 2 Brains 2 Mind 2 Me

The DISC1 mouse is a major step forward in a translational research path towards understanding how genes contribute to the risk of complex mental disorders such as schizophrenia. The latest mouse (see PNAS – Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans by Hikida et al.) attempts to replace the normal mouse gene with a human mutation. The deficits parallel human abnormalities in a remarkable way. Note, however, that Joseph Gogos and colleagues (including my one-time boss Maria Karayiorgou) have shown (see PNAS -Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice by Hiroko et al.) that an ostensibly normal mouse inbred strain (normal, that is, if you’re inbred for one, and a mouse, for another) carries a truncated form of DISC1. Both of these mouse models show deficits in frontal cortex dependent behaviors but, together, they also demonstrate how the many interacting genes in the background can modify and ameliorate the effects of a single mutation. Do the genes that modify DISC1 in mice modify risk in humans?