Developmental Genes and Regulatory Proteins, Domains of Cognitive Impairment in Schizophrenia Spectrum Psychosis and Implications for Antipsychotic Drug Discovery: The Example of Dysbindin-1 Isoforms and Beyond

Alongside positive and negative symptomatology, deficits in working memory, attention, selective learning processes, and executive function have been widely documented in schizophrenia spectrum psychosis. These cognitive abnormalities are strongly associated with impairment across multiple function domains and are generally treatment-resistant. The DTNBP1 (dystrobrevin-binding protein-1) gene, encoding dysbindin, is considered a risk factor for schizophrenia and is associated with variation in cognitive function in both clinical and nonclinical samples. Downregulation of DTNBP1 expression in dorsolateral prefrontal cortex and hippocampal formation of patients with schizophrenia has been suggested to serve as a primary pathophysiological process. Described as a “hub,” dysbindin is an important regulatory protein that is linked with multiple complexes in the brain and is involved in a wide variety of functions implicated in neurodevelopment and neuroplasticity. The expression pattern of the various dysbindin isoforms (-1A, -1B, -1C) changes depending upon stage of brain development, tissue areas and subcellular localizations, and can involve interaction with different protein partners. We review evidence describing how sequence variation in DTNBP1 isoforms has been differentially associated with schizophrenia-associated symptoms. We discuss results linking these isoform proteins, and their interacting molecular partners, with cognitive dysfunction in schizophrenia, including evidence from drosophila through to genetic mouse models of dysbindin function. Finally, we discuss preclinical evidence investigating the antipsychotic potential of molecules that influence dysbindin expression and functionality. These studies, and other recent work that has extended this approach to other developmental regulators, may facilitate identification of novel molecular pathways leading to improved antipsychotic treatments.