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Donohoe G, Morris DW, De Sanctis P, Magno E, Montesi JL, Garavan HP, Robertson IH, Javitt DC, Gill M, Corvin AP, Foxe JJ. Early Visual Processing Deficits in Dysbindin-Associated Schizophrenia. Biol Psychiatry. 2007 Oct 16 ; Pubmed Abstract

Comments on News and Primary Papers
Comment by:  Philip Seeman (Disclosure)
Submitted 29 November 2007
Posted 29 November 2007
  I recommend the Primary Papers

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 amphetamine, phencyclidine, cocaine, caffeine or corticosterone, birth injury, social isolation, and more than 15 gene deletions in pathways for glutamate (NMDA), dopamine, GABA, acetylcholine, and norepinephrine. Although the proportion of D2High receptors invariably increases markedly, the total number of D2 receptors is generally unchanged, slightly reduced, or modestly elevated.

This publication for the first time bridges the hitherto wide gap between genetics and the antipsychotic targeting of the main cause of psychotic signs and symptoms, which is excessive D2 activity, presumably that of D2High, the functional component of D2.

References:

Seeman P, Weinshenker D, Quirion R, Srivastava LK, Bhardwaj SK, Grandy DK, Premont RT, Sotnikova TD, Boksa P, El-Ghundi M, O'dowd BF, George SR, Perreault ML, Männistö PT, Robinson S, Palmiter RD, Tallerico T. Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis. Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3513-8. Epub 2005 Feb 16. Abstract

Seeman P, Schwarz J, Chen JF, Szechtman H, Perreault M, McKnight GS, Roder JC, Quirion R, Boksa P, Srivastava LK, Yanai K, Weinshenker D, Sumiyoshi T. Psychosis pathways converge via D2high dopamine receptors. Synapse. 2006 Sep 15;60(4):319-46. Review. Abstract

View all comments by Philip SeemanComment by:  Christoph Kellendonk
Submitted 4 December 2007
Posted 4 December 2007

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 the molecular consequences of decreased dysbindin levels in cell culture.

They found that downregulation of dysbindin increases D2 receptor density in the outer cell membrane, suppresses dopamine-induced D2 receptor internalization, and increases D2 receptor signaling. The study is very promising but requires further confirmation.

How specific are the observed effects for D2 receptors? Because dysbindin is involved in both membrane trafficking and degradation of synaptic vesicles, knocking down dysbindin in growing cells may affect many physiological processes, one of them being D2 receptor signaling. Does quinpirole treatment differentially affect GTPgS incorporation in siRNA and control cells? This would be a more immediate way of looking at D2 signaling than measuring CREB phosphorylation. And, of course, the most important question is, What will happen in vivo? Maybe the sandy mouse, which carries a deletion in the dysbindin gene, could be of help here. Using these mice for a similar line of experiments may answer this question.

Iizuka and colleagues found an exciting new functional interaction between two major molecules involved in schizophrenia. I believe that these are the kind of interactions we have to look for if we want to understand complex genetic disorders such as schizophrenia.

View all comments by Christoph Kellendonk