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

Waddington, John L.; Zhen, Xuechu; O'Tuathaigh, Colm M. P.
January 2020
Frontiers in Pharmacology;1/29/2020, p1
Academic Journal
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.


Related Articles

  • Dandy-Walker Malformation-Like Condition Revealed by Refractory Schizophrenia: A Case Report and Literature Review. Tréhout, Maxime; Zhang, Norbert; Blouet, Marie; Borha, Alin; Dollfus, Sonia // Neuropsychobiology;2018/2019, Vol. 77 Issue 2, p59 

    Introduction: Dandy-Walker malformation is a rare congenital malformation involving cystic dilatation of the fourth ventricle, enlarged posterior fossa, complete or partial agenesis of the cerebellar vermis, elevated tentorium cerebelli, and hydrocephalus. Previous research highlighted a...

  • Influence of Aripiprazole, Risperidone, and Amisulpride on Sensory and Sensorimotor Gating in Healthy 'Low and High Gating' Humans and Relation to Psychometry. Csomor, Philipp A; Preller, Katrin H; Geyer, Mark A; Studerus, Erich; Huber, Theodor; Vollenweider, Franz X // Neuropsychopharmacology;Sep2014, Vol. 39 Issue 10, p2485 

    Despite advances in the treatment of schizophrenia spectrum disorders with atypical antipsychotics (AAPs), there is still need for compounds with improved efficacy/side-effect ratios. Evidence from challenge studies suggests that the assessment of gating functions in humans and rodents with...

  • Mismatch Negativity Indices as a Prognostic Factor for Remission in Schizophrenia. Ji Sun Kim; Young Joon Kwon; Hwa Young Lee; Ho-Sung Lee; Sungkean Kim; Se-hoon Shim // Clinical Psychopharmacology & Neuroscience;Feb2020, Vol. 18 Issue 1, p127 

    Objective: Mismatch negativity (MMN) is known to be associated with neuro-cognition and functional outcomes. Remission and recovery rates are related to the neuro-cognition of patients with schizophrenia. The present study explored the relationship of MMN with remission in patients with...

  • In Vitro and In Vivo Models for the Investigation of Potential Drugs Against Schizophrenia. Kaczor, Agnieszka A.; Kȩdzierska, Ewa; Koszła, Oliwia; Targowska-Duda, Katarzyna M. // Biomolecules (2218-273X);Jan2020, Vol. 10 Issue 1, p1 

    Schizophrenia (SZ) is a complex psychiatric disorder characterized by positive, negative, and cognitive symptoms, and is not satisfactorily treated by current antipsychotics. Progress in understanding the basic pathomechanism of the disease has been hampered by the lack of appropriate models. In...

  • Diagnóstico diferencial de psicosis de inicio a los 64 años con síntomas tipo esquizofrenia. Villero Luque, Sonia; Vivero Poveda, Ángela; González-Molinier, Manuel; García-Bernardo, Enrique // Revista Colombiana de Psiquiatria;Sep2010, Vol. 39 Issue 3, p617 

    Psychosis that starts after the age of 60 years has incited diagnostic controversies since the beginning of psychiatry. One of the major discussion subjects has been the validity of the application of the diagnosis of schizophrenia to that age range. Nowadays, there is an international consensus...

  • Roles of prefrontal cortical GABAergic interneurons in psychosis and cognitive deficits in schizophrenia. Tanaka, Shoji // BMC Neuroscience;2008 Supplement 1, Vol. 9, Special section p1 

    The article focuses on a study on the role of gamma-aminoburytic acid (GABA)ergic dysregulation in psychosis and cognitive deficits in schizophrenia. It was stated that chandelier neurons would restrain hyperactivity by applying hyper-dopaminergic neurotransmission which is linked to psychotic...

  • Pharmacology of "atypicality" of antipsychotic drugs: status and perspectives. Newman-Tancredi, Adrian; Kleven, Mark S. // Archives of Psychiatry & Psychotherapy;Dec2010, Vol. 12 Issue 4, p5 

    "Atypical" antipsychotics are antagonists at serotonin 5-HT2A and dopamine D2 receptors. However, their effects on negative symptoms and cognitive deficits remain modest and they disrupt metabolic function. Recent drugs, such as aripiprazole, perospirone, bifeprunox, lurasidone and cariprazine...

  • Memory-Prediction Errors and Their Consequences in Schizophrenia. Kraus, Michael S.; Keefe, Richard S. E.; Krishnan, Ranga K. R. // Neuropsychology Review;Sep2009, Vol. 19 Issue 3, p336 

    Cognitive deficits play a central role in the onset of schizophrenia. Cognitive impairment precedes the onset of psychosis in at least a subgroup of patients, and accounts for considerable dysfunction. Yet cognitive deficits as currently measured are not significantly related to hallucinations...

  • Social function in schizophrenia and schizoaffective disorder: Associations with personality, symptoms and neurocognition. Lysaker, Paul H.; Davis, Louanne W. // Health & Quality of Life Outcomes;2004, Vol. 2, p15 

    Background: Research has indicated that stable individual differences in personality exist among persons with schizophrenia spectrum disorders predating illness onset that are linked to symptoms and self appraised quality of life. Less is known about how closely individual differences in...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics