The publication by Iizuka and colleagues is an important advance toward unraveling the basic biology of psychosis in general, and schizophrenia in particular. This is because they have found that a pathway known to be genetically associated with schizophrenia can alter the surface expression of dopamine D2 receptors. D2 continues to be the main target for all antipsychotic drugs (including aripiprazole and even the new Lilly glutamate agonists that have a potent affinity for D2High receptors).

In fact, the authors of this excellent study may do well to go one step further by testing whether the downregulation of dysbindin actually increases the proportion of D2 receptors that are in the high-affinity state, namely D2High. This is because all schizophrenia animal models markedly increase the proportion of D2High receptors by 100 to 900 percent (Seeman et al., 2005; Seeman et al., 2006). This generalization holds for animal models based on brain lesions, sensitization by...  Read more

View all comments by Philip Seeman

The study by Iizuka and colleagues is indeed very interesting. It suggests that one of the most promising risk genes for schizophrenia, the dysbindin gene, may functionally interact with dopamine D2 receptors. The D2 receptor itself is an old candidate in the study of schizophrenia, mostly because until very recently all antipsychotic medication had been directed against D2 receptors. But in addition, PET imaging studies have shown that the density and occupancy of D2 receptors is increased in drug-free and drug-naïve patients with schizophrenia.

How could this increase arise? In a subpopulation of patients it may be due to a polymorphism in the D2 receptor gene, the C957T polymorphism. The C-allele increases mRNA stability and has been found to be associated with schizophrenia, though obviously not all patients carry the C-allele. Iizuka and colleagues found an independent way in which the genetic risk factor dysbindin may upregulate D2 receptor signaling. Because dysbindin is downregulated in the brains of patients with schizophrenia, they used siRNA technology to study...  Read more

View all comments by Christoph Kellendonk