Forum Discussion: How Might Dysbindin Affect the Schizophrenic Brain?
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In our Forum Discussion “journal club” series, the editors of Neuropsychopharmacology provide access to the full text of a recent article. An introduction by Monsheel Sodhi, Assistant Professor, Department of Psychiatry and Behavioral Neurobiology, UAB, gets us started, and then it's up to our readers to share their ideas and insights, questions, and reactions to the selected paper. So read on….
Donohoe G, Frodl T, Morris D, Spoletini I, Cannon DM, Cherubini A, Caltagirone C, Bossù P, McDonald C, Gill M, Corvin AP, Spalletta G. Reduced Occipital and Prefrontal Brain Volumes in Dysbindin-Associated Schizophrenia. Neuropsychopharmacology. 2009 Sep 30. [Epub ahead of print]. Abstract
Our thanks to Nature Journals for allowing this article to be posted for discussion at SRF.
Marquis Vawter — Posted 15 December 2009
Gary Donohoe — Posted 17 December 2009
Joel Kleinman — Posted 13 February 2010
By Monsheel Sodhi, Assistant Professor, Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham
This paper reports new data that may increase interest in the move toward using genetic markers to predict more focused phenotypes in schizophrenia. The heritability of morphological changes in the brains of schizophrenia patients has been found to be high (Peper et al., 2007). Therefore, the authors of the current paper have investigated one of the candidate genes for schizophrenia identified by positional cloning, the gene encoding dystrobrevin-binding protein 1 (dysbindin).
There have been many case-control studies published that have produced conflicting data on the genetic association between dysbindin and schizophrenia; for example, at least 19 studies have been positive (see www.SZgene.org). However, in the current paper, the authors show that the gene encoding dysbindin is associated with altered brain morphology, as measured by voxel-based morphometry. Subjects carrying a risk haplotype comprising the dysbindin SNPs P1655 (rs2619539), P1635 (rs3213207), and SNP66961 (rs2619538) (abbreviated to C-A-T) have reductions in gray matter volumes of the right dorsolateral prefrontal cortex and left occipital cortex.
The same risk haplotype may be a marker in a subset of the schizophrenia population who have a specific combination of symptoms due to particular structural and/or developmental defects in the brain. These morphological changes could explain certain symptoms exhibited by patients, particularly cognitive and negative ones, which have previously been associated with the C-A-T haplotype of dysbindin (Corvin et al., 2008).
Dysbindin is expressed in forebrain glutamate neurons. It interacts with proteins involved in the presynaptic trafficking of vesicles and exocytosis. In fact, mice with a null mutation of the dysbindin gene have been reported to show impaired spatial working memory relative to wild-type controls (Jentsch et al., 2009).
Taken together, these data indicate that dysbindin impacts brain functions such as working memory. This may be due to impaired brain development via dysregulation of presynaptic glutamatergic transmission. Therefore, functional genetic variation of dysbindin could contribute to some of the more devastating symptoms experienced by patients with schizophrenia.
If these findings are replicated, many questions will need to be addressed. For instance, by what mechanism(s) could dysbindin change gray matter volume in these brain regions? Could patients who have schizophrenia and abnormal gray matter volume in these specific regions have a subtype of schizophrenia that is attributable to altered dysbindin?
Peper JS, Brouwer RM, Boomsma DI, Kahn RS, Hulshoff Pol HE. Genetic influences on human brain structure: a review of brain imaging studies in twins. Hum Brain Mapp. 2007;28(6):464-73. Abstract
Corvin A, Donohoe G, Nangle JM, Schwaiger S, Morris D, Gill M. A dysbindin risk haplotype associated with less severe manic-type symptoms in psychosis. Neurosci Lett. 2008;431(2):146-9. Abstract
Jentsch JD, Trantham-Davidson H, Jairi C, Tinsley M, Cannon TD, Lavin A. Dysbindin modulates prefrontal cortical glutamatergic circuits and working memory function in mice. Neuropsychopharmacology. 2009 July 29. Abstract