[Risk genes for schizophrenia and neuronal plasticity: molecular target for antipsychotic discovery]

Abstract

The dysbindin-1 gene (DTNBP1: dystrobrevin binding protein 1) has been identified as a susceptibility gene for schizophrenia. Genetic variations of DTNBP1 were reported to be associated with several intermediate phenotypes such as general cognitive ability, memory, and regional brain activation and cortical volume. In studies on postmortem brain tissue, decreased expression levels of dysbindin-1 were shown in patients with schizophrenia. Risk genetic variation of dysbindin for schizophrenia was associated with reduced expression of dysbindin in human brains. These data indicate that the dysbindin-1 gene may confer susceptibility to schizophrenia through reduced expression and that sandy mice lacking dysbindin-1 protein could be a unique animal model of schizophrenia. Sandy mice were less active, had heightened anxiety-like response, demonstrated deficits in social interaction and showed impaired long-term memory retention and working memory. Sandy mice demonstrated lower levels of dopamine, but not glutamate, in restricted brain regions. Several neuronal functions of dysbindin were reported, such as neurotransmitter release, direct interaction with presynaptic molecules, neuroprotection, cytosckeletal organization, and gene expression. To investigate dysbindin function in the brain could shed light on the etiology of schizophrenia and lead us to new hypotheses, novel diagnostic tools, and more effective therapies for the disorder.