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

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

Astrocytic Regulation of Basal Ganglia Dopamine/D2-Dependent Behaviors

“…Dys1 has been linked to neuronal dopaminergic and glutamatergic signaling 17,[20][21][22][23][24] . However, drosophila dysbindin (dDys) has shown dichotomic regulation of glutamatergic and dopaminergic transmission, with the latter involving glial cells 25 .…”

Long-lasting rescue of schizophrenia-relevant cognitive impairments via risperidone-loaded microPlates

“…μPL are characterized for their morphological, physico-chemical, and pharmacological features. To test their in vivo efficacy, μPL are intraperitoneally injected in heterozygous knockout mice for dysbindin-1 (Dys ±), a clinically relevant mouse model of cognitive and psychiatric liability, with proved evidence of modulatory responses to antipsychotic drugs in mice and human patients [20][21][22][23][24].…”

A human iPSC-astroglia neurodevelopmental model reveals divergent transcriptomic patterns in schizophrenia

“…A combination of genetic and environmental factors is likely to play a role in disrupting the normal morphogenesis of the fetal brain. In addition, an interplay of various exogenous and endogenous components may affect CNS development and maturation, giving rise to the biological basis from which psychosis and other clinical symptoms emerge, most commonly during adolescence and early adulthood [ 9 , 10 ].…”