Variation in the gene encoding dysbindin-1 (i.e., dystrobrevin-binding protein 1: DTNBP1) has frequently been associated with schizophrenia. Several studies have also found that dysbindin-1 gene and protein expression are altered in two affected brain areas in that disorder (i.e., the dorsolateral prefrontal cortex and the hippocampal formation). To provide the context and information needed for further study of these phenomena, this chapter provides the first comprehensive review of the dysbindin protein family. The family has three paralogs (dysbindin-1, -2, and -3), each of which is encoded by a different gene and expressed in more than one isoform. There are at least eight family members in humans (dysbindin-1A, -1B, -1C, -2A, -2B, -2C, -3A, and -3B).
Dysbindin-1 is distinguished from other paralogs of the dysbindin family by the presence of a coiled coil domain important in interactions with other proteins. We focus on this paralog since it is the only one associated with schizophrenia thus far. Its gene, DTNBP1, has three major transcripts encoding isoforms running on western blots at approximately 50, 37, and 33 kDa (=dysbindin-1A, -1B, and -1C, respectively). The ∼37 kDa isoform cannot be studied in mice, which appear to lack an ortholog of human dysbindin-1B. While present in neuronal cell bodies throughout the central nervous system, dysbindin-1 is prominently enriched only in certain synaptic fields, mainly those known to be dopaminergic, glutamatergic, and/or GABAergic. In synaptic tissue of the human brain, dysbindin-1A is mainly concentrated in postsynaptic density fractions, dysbindin-1B in synaptic vesicle fractions, and dysbindin-1C in both those fractions. It is unknown if the isoforms differ in binding partners, but they are collectively known to bind a large number of proteins, including several proteins belonging to the biogenesis of lysosome-related organelles complex 1 (BLOC-1).
An animal model of dysbindin-1’s functions is available in the sandy (sdy) mouse, which has a naturally occurring deletion mutation in DTNBP1 that leads to loss of dysbindin-1 in homozygous mice, which also shows a loss or reduction in other BLOC-1 binding partners. Among the many abnormalities of homozygous sdy mice are increased dopamine transmission in limbic tissue, decreased glutamate release and NMDA-mediated postsynaptic currents in prefrontal cortex, smaller excitatory evoked responses and loss of inhibitory responses after stimulation in the hippocampal formation, and severe deficits in spatial learning and memory processes. While the homozygous sdy mouse shares behavioral and biological features of schizophrenia, it is currently unclear if it serves an animal model of that disorder. It may, however, model cognitive aspects of schizophrenia.
Dysbindin-1 may have diverse functions. Among these are the promotion of cell growth and proliferation, protection against neuronal apoptosis, facilitation of axon, dendrite, and dendritic spine growth, regulation of AP-3 cargo transport to lysosome-related organelles (including reserve pool synaptic vesicles), facilitation of glutamate release and inhibition of dopamine release, regulation of constitutive D2R cell surface expression, and promotion of cognitive processes.
While the association between genetic variation in DTNBP1 and schizophrenia has been questioned recently, there is mounting evidence that the associations found reflect actual susceptibility variants in the gene. Even in the absence of such variants, altered dysbindin-1 gene and protein expression have been found in the dorsolateral prefrontal cortex and hippocampal formation of schizophrenia cases. These changes may contribute to the pathophysiology of the disorder by altering brain development, dopaminergic and glutamatergic transmission, functional connectivity of neuronal populations in the cerebral cortical and the hippocampal formation, and cognition.