Variance in neurocognitive performance is associated with dysbindin-1 in schizophrenia: A preliminary study

Abstract

Susceptibility genes for schizophrenia have been hypothesised to mediate liability for the disorder at least partly by influencing cognitive performance. We investigated the association between genotype and cognitive performance for a Dysbindin risk haplotype which is associated with schizophrenia in our sample. Fifty-two patients with schizophrenia or schizoaffective disorder (24 risk haplotypes carriers versus 28 non-risk haplotype carriers) were assessed in areas of cognition showing evidence of familial deficits in schizophrenia. Verbal and spatial memory, working memory, and attentional control was assessed using selected measures from the Weschler memory scale (WMS), Cambridge automated test battery (CANTAB), continuous performance test (CPT), and a simple go/no-go task. Pre-morbid IQ was also assessed using the Weschler Test of Adult Reading (WTAR). Patients carrying the Dysbindin risk haplotype showed significantly lower spatial working memory performance than patients who were non-risk carriers, with genotype explaining 12% of variance in performance. Our study suggests that the increased risk for schizophrenia associated with dysbindin may be partly mediated by its influence on pre-frontal function.

Early Visual Processing Deficits in Dysbindin-Associated Schizophrenia

“…Although early stages of perceptual processing (from as early as 50 -100 msec poststimulus) serve an important role in "spotlighting" of relevant information for later processing, these early processing stages (from 70 msec onward) appear to be reciprocally modulated by higher processing areas ( 26). It is therefore interesting that in our sample, a twin association between a dysbindin risk haplotype and both sensory and higher cognitive processes is evidenced (previously) by its association with poorer visuospatial working memory ( 8) and in this study by its association with early visual relationship between early sensory and higher cognitive funcduring spatial working memory tasks. Conversely, an inability to maintain context during later stages of context processing leads stages of visual processing.…”

“…Variants in dysbindin that are ciated with poorer general cognitive performance in controls ( 6) with schizophrenia ( 6,8 been inconsistent across groups ( 20). Our study extends these previous reports by indicating that variation at the gene may play cognitive and sensory processes both in patients and control subjects suggests a more general role for dysbindin in brain with most brain-expressed genes, dysbindin is widely expressed http://www.brain-map.org ) ( 2-4), and we view this as consistent with a global involvement in presynaptic glutamate availability.…”

“…Variants at dysbindin associated with schizophrenia risk have been inconsistent across studies (20); the C-A-T risk haplotype in our sample is associated with reduced cortical expression of the gene, poorer educational attainment, and poorer spatial working memory ( 2,8). Given these previous associations, we hypothesized that carriers of the risk haplotype would have a signi cantly attenuated P1 response compared with patients who were nonrisk carriers.…”

“…This suggests that risk variants may have a synaptic consequence in terms of glutamate availability. Recently, dysbindin risk variants have been associated with poorer performance in higher cognitive domains in controls ( 6 -7) and with both general and domain-speci c de cits (e.g., spatial working memory dysfunction) in schizophrenia ( 6,8).…”

Dysbindin-1 mutant mice implicate reduced fast-phasic inhibition as a final common disease mechanism in schizophrenia

“…More broadly, reduction in dysbindin-1 expression has been found in the schizophrenia population (16,27,29), indicating that reduced dysbindin-1 protein levels may be a common disease trait of schizophrenia. Haplotypes of DTNB1 associated with elevated protein expression are associated with enhanced working memory performance in humans (30), whereas risk haplotypes are associated with reduced spatial memory (31). This role for dysbindin-1 has been attributed to changes in excitatory drive, because dysbindin-1 is typically described as highly concentrated in a subset of glutamatergic synaptic vesicles and postsynaptic densities (30,32,33).…”