DTNBP1 (dysbindin) gene variants modulate prefrontal brain function in schizophrenic patients – support for the glutamate hypothesis of schizophrenias

Abstract

Dysbindin (DTNBP1) is a recently characterized protein that seems to be involved in the modulation of glutamatergic neurotransmission in the human brain, thereby influencing prefrontal cortex function and associated cognitive processes. While association, neuroanatomical and cellular studies indicate that DTNBP1 might be one of several susceptibility genes for schizophrenia, the effect of dysbindin on prefrontal brain function at an underlying neurophysiological level has not yet been explored for these patients. The NoGo-anteriorization (NGA) is a topographical event-related potential measure, which has been established as a valid neurophysiological marker of prefrontal brain function. In the present study, we investigated the influence of seven dysbindin gene variants on the NGA in a group of 44 schizophrenic patients. In line with our a priori hypothesis, one DTNBP1 polymorphism previously linked to schizophrenia (rs2619528) was found to be associated with changes in the NGA; however, the direction of this association directly contrasts with our previous findings in a healthy control sample. This differential impact of DTNBP1 gene variation on prefrontal functioning in schizophrenic patients vs. healthy controls is discussed in terms of abnormal glutamatergic baseline levels in patients suffering from schizophrenic illnesses. This is the first report on a role of DTNBP1 gene variation for prefrontal functioning at a basic neurophysiological level in schizophrenic patients. An impact on fundamental processes of cognitive response control may be one mechanism by which DTNBP1 gene variants via glutamatergic transmission contribute to the pathophysiology underlying schizophrenic illnesses.

Structural and functional neuroimaging phenotypes in dysbindin mutant mice

“…Genetic variation in the DTNBP1 locus has also been associated with functional changes in frontal regions measured using event related potentials (ERP) in individuals with (Fallgatter et al, 2010) and without (Fallgatter et al, 2006) schizophrenia.…”

Current Strategies in Diagnosis of Inherited Storage Pool Defects

“…However, pulmonary function and computed tomography (CT) chest scans were normal [38]. Interestingly, DTNBP1 (dystrobrevin-binding protein 1, HPS7) gene variants were shown to be associated with schizophrenia; however, this correlation is controversial [39,40]. A Pakistani family with several HPS8 patients, all carrying the same mutation, did not demonstrate further clinical complications except Sandrock/Zieger ondary wave of platelet aggregation is impaired and platelets show an increased ATP-to ADP-ratio and a decreased amount of serotonin and calcium.…”

Association of genetic variations in DTNBP1 with cognitive function in schizophrenia patients and healthy subjects

“…Several research groups have reported an association between DTNBP1 and cognitive function in schizophrenia patients [Burdick et al, 2006[Burdick et al, , 2007Donohoe et al, 2007;Zinkstok et al, 2007;Alfimova et al, 2010;Fallgatter et al, 2010;Fatjo-Vilas et al, 2011] (Table I). However, other studies yielded negative results [Peters et al, 2008;Hashimoto et al, 2009Hashimoto et al, , 2010Strohmaier et al, 2010].…”