Abstract
BackgroundAn increasing number of studies report associations between variation in DTNBP1, a top candidate gene in schizophrenia, and both the clinical symptoms of the disorder and its cognitive deficits. DTNBP1 encodes dysbindin-1, reduced levels of which have been found in synaptic fields of schizophrenia cases. This study determined whether such synaptic reductions are isoform-specific.Methodology/Principal FindingsUsing Western blotting of tissue fractions, we first determined the synaptic localization of the three major dysbindin-1 isoforms (A, B, and C). All three were concentrated in synaptosomes of multiple brain areas, including auditory association cortices in the posterior half of the superior temporal gyrus (pSTG) and the hippocampal formation (HF). Tests on the subsynaptic tissue fractions revealed that each isoform is predominantly, if not exclusively, associated with synaptic vesicles (dysbindin-1B) or with postsynaptic densities (dysbindin-1A and -1C). Using Western blotting on pSTG (n = 15) and HF (n = 15) synaptosomal fractions from schizophrenia cases and their matched controls, we discovered that synaptic dysbindin-1 is reduced in an isoform-specific manner in schizophrenia without changes in levels of synaptophysin or PSD-95. In pSTG, about 92% of the schizophrenia cases displayed synaptic dysbindin-1A reductions averaging 48% (p = 0.0007) without alterations in other dysbindin-1 isoforms. In the HF, by contrast, schizophrenia cases displayed normal levels of synaptic dysbindin-1A, but 67% showed synaptic reductions in dysbindin-1B averaging 33% (p = 0.0256), while 80% showed synaptic reductions in dysbindin-1C averaging 35% (p = 0.0171).Conclusions/SignificanceGiven the distinctive subsynaptic localization of dysbindin-1A, -1B, and -1C across brain regions, the observed pSTG reductions in dysbindin-1A are postsynaptic and may promote dendritic spine loss with consequent disruption of auditory information processing, while the noted HF reductions in dysbindin-1B and -1C are both presynaptic and postsynaptic and could promote deficits in spatial working memory.
Highlights
Among the many genes which may promote development of schizophrenia, DTNBP1 remains among the top candidates [1,2] and is among the most intensively investigated
The present study demonstrates (1) that the three major dysbindin-1 isoforms are synaptically located in the human brain, (2) that they are differentially distributed in synaptic compartments, (3) that one or more of these pre- and/or post-synaptically localized isoforms are significantly reduced in synaptosomes of the
Dysbindin-1 isoform reductions observed in synaptosomes of schizophrenia cases indicate the subsynaptic compartments where those reductions occurred
Summary
Among the many genes which may promote development of schizophrenia, DTNBP1 (dystrobrevin binding protein 1) remains among the top candidates [1,2] and is among the most intensively investigated. An increasing number of studies report that several of these DTNBP1 risk variants are associated with severity of the positive symptoms (e.g., delusions and hallucinations) and especially the negative symptoms (e.g., flattened affect and social withdrawal) of schizophrenia [7,8,9,10] Such genetic variants are associated with severity of cognitive deficits in this disorder [3,11,12,13,14]. How DTNBP1 risk SNPs or haplotypes may affect dysbindin-1 is still unknown, but it is known that levels of this protein are lower in two brain areas dysfunctional in schizophrenia. The degree of tissue shrinkage is significantly correlated with the degree of memory and executive function deficits in the case of HF volume reductions [35,36,37,38] and with the frequency and severity of auditory hallucinations in the case of STG volume reductions [39,40,41,42]
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