Dysbindin-1 in dorsolateral prefrontal cortex of schizophrenia cases is reduced in an isoform-specific manner unrelated to altered dysbindin-1 gene expression

Abstract

DTNBP1 (dystrobrevin binding protein 1) remains one of the top candidate genes in schizophrenia. Reduced expression of this gene and the protein it encodes, dysbindin-1, has been reported in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia cases. It has not been established, however, if all dysbindin-1 isoforms are reduced in the DLPFC or if the reduction is associated with reduced DTNBP1 gene expression. Using Western blotting of whole-tissue lysates of the DLPFC with antibodies differentially sensitive to the three major isoforms of this protein (dysbindin-1A, -1B, and -1C), we found no significant differences between our schizophrenia cases and matched controls in dysbindin-1A or -1B, but did find a mean 46% reduction in dysbindin-1C in 71% of 28 case-control pairs (p = 0.022). This occurred in the absence of the one DTNBP1 risk haplotype for schizophrenia reported in the US and without alteration in levels of dysbindin-1C transcripts. Conversely, the absence of changes in the dysbindin-1A and -1B isoforms was accompanied by increased levels of their transcripts. We thus found no correspondence between alterations in dysbindin-1 gene and protein expression, the latter of which might be due to posttranslational modifications such as ubiquitination. Reduced DLPFC dysbindin-1C in schizophrenia probably occurs in PSDs, where we find dysbindin-1C to be heavily concentrated in the human brain. Given known postsynaptic effects of dysbindin-1 reductions in the rodent homolog of the prefrontal cortex, these findings suggest that reduced dysbindin-1C in the DLPFC may contribute to cognitive deficits of schizophrenia by promoting NMDA receptor hypofunction.