Abstract
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.
Highlights
Schizophrenia, Cognitive Impairment, and Functional DisabilitySchizophrenia is a complex psychiatric disorder that is the exemplar of a broader spectrum of psychotic illness in which interactive contributions from genetic and environmental factors play critical roles in etiology and pathobiology (Owen et al, 2016); hereafter, we use the term schizophrenia as shorthand for this spectrum of illness
Shao et al (2011) reported that neuronal disruption of dysbindin function in drosophila was associated with hypoglutamatergic transmission and deficits in working memory, while disruption of dysbindin function in glial cells was associated with hyperdopaminergia and locomotor hyperactivity; this latter effects was mediated via a reduction in the protein Ebony, a glia-specific beta-alanyl biogenic amine synthetase involved in metabolic degradation of biogenic amines in the nervous system
While sdy/B6 mutants displayed lower CaMKII and CaMKKb protein levels in mPFC, control mice chronically treated with a D2 receptors (D2R) agonist showed the same specific reductions. These results suggest that some effects of dysbindin on cognition, associated with changes in cortical activity and CaMK components of the mPFC, are induced via upregulation of D2R
Summary
Schizophrenia is a complex psychiatric disorder that is the exemplar of a broader spectrum of psychotic illness in which interactive contributions from genetic and environmental factors play critical roles in etiology and pathobiology (Owen et al, 2016); hereafter, we use the term schizophrenia as shorthand for this spectrum of illness. DTNBP1 haplotypes are associated with greater decline in IQ (Burdick et al, 2007) and impairment in spatial working memory (Donohoe et al, 2007; Donohoe et al, 2008; Donohoe et al, 2010) and attentional/vigilance (Baek et al, 2012), verbal and visual working memory and speed of processing (Varela-Gomez et al, 2015), as well as executive function (Scheggia et al, 2018) Such findings have been less evident on subdividing schizophrenia patients into cognitive-deficit and cognitivesparing groups (Peters et al, 2008). Despite preliminary evidence to suggest dysbindin involvement in cognitive function in patients with brain tumours (Correa et al, 2016), there is a paucity of studies examining the role of dysbindin in other neurological and neuropsychiatric disorders where symptoms include cognitive dysfunction
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