This paper demonstrates several important shifts in research strategies for schizophrenia. Many previous studies of candidate genes in the illness have chosen their targets based on concepts of the mechanism of action of antipsychotic drugs, or by virtue of the proximity of a gene to a genetic linkage site defined with anonymous markers. The choice of candidate gene here is based on a wide range of neurobiological evidence, including studies of gene expression and protein levels. As well, the authors do not limit their study to one gene; instead, they expand their investigation to include plausibly interacting gene targets. Analysis of complex disorders will likely need more than simple models, and the approach here is worth noting.

The gap still remains between the DNA-mRNA approaches and protein analysis. Gene expression is one factor determining mRNA levels. However, especially in human brain tissue samples, many other antemortem and postmortem factors contribute to the measured level of mRNA. The meaning of gene expression measures obtained for...  Read more

This paper demonstrates several important shifts in research strategies for schizophrenia. Many previous studies of candidate genes in the illness have chosen their targets based on concepts of the mechanism of action of antipsychotic drugs, or by virtue of the proximity of a gene to a genetic linkage site defined with anonymous markers. The choice of candidate gene here is based on a wide range of neurobiological evidence, including studies of gene expression and protein levels. As well, the authors do not limit their study to one gene; instead, they expand their investigation to include plausibly interacting gene targets. Analysis of complex disorders will likely need more than simple models, and the approach here is worth noting.

The gap still remains between the DNA-mRNA approaches and protein analysis. Gene expression is one factor determining mRNA levels. However, especially in human brain tissue samples, many other antemortem and postmortem factors contribute to the measured level of mRNA. The meaning of gene expression measures obtained for oligodendrocyte/myelination-related genes from samples comprising largely gray matter is not entirely certain. The role of oligodendrocytes in gray matter may deserve more attention.

The genetic evidence presented here for an interaction between OLIG2 and ErbB4 is intriguing. A recent paper from Steve Arnold’s group indicated the neuregulin-1−ErbB4 signaling pathway appears to be overactive in schizophrenia, with consequences for NMDA receptor function (Hahn et al., 2006). Although the analysis in their paper focused on neurons, if a similarly overactive pathway was operative in oligodendrocytes, inhibition of myelination might be a predicted outcome (Sussman et al., 2005), with downregulation of a host of oligodendrocyte/myelination-related genes as a consequence. Of further interest, NMDA receptors may have important roles in oligodendrocytes as well as in neurons (Matute, 2006).

References:

Hahn CG, Wang HY, Cho DS, Talbot K, Gur RE, Berrettini WH, Bakshi K, Kamins J, Borgmann-Winter KE, Siegel SJ, Gallop RJ, Arnold SE. Altered neuregulin 1-erbB4 signaling contributes to NMDA> receptor hypofunction in schizophrenia. Nat Med. 2006 Jul;12(7):824-8. Epub 2006 Jun 11. Abstract

Sussman CR, Vartanian T, Miller RH. The ErbB4 neuregulin receptor mediates suppression of oligodendrocyte maturation. J Neurosci. 2005 Jun 15;25(24):5757-62. Abstract

Matute C. Oligodendrocyte NMDA receptors: a novel therapeutic target. Trends Mol Med. 2006 Jul;12(7):289-92. Epub 2006 Jun 5. Abstract