Dysbindin-1 modulates prefrontal cortical activity and schizophrenia-like behaviors via dopamine/D2 pathways

• Published in: Molecular psychiatry Vol. 17; no. 1; pp. 85 - 98
• Main Authors: Papaleo, F, Yang, F, Garcia, S, Chen, J, Lu, B, Crawley, J N, Weinberger, D R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2012; Nature Publishing Group
• Subjects: 631/378/1457/1945; 631/378/1689/1761; 631/92/436/2388; Action Potentials - drug effects; Action Potentials - genetics; Adult and adolescent clinical studies; Amphetamine - adverse effects; Animals; Behavior; Behavioral Sciences; Binding proteins; Biological and medical sciences; Biological Psychology; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Carrier Proteins - genetics; Cognition & reasoning; Cognitive ability; Disease Models, Animal; Dopamine; Dopamine - metabolism; Dopamine Agents - pharmacology; Dopaminergic mechanisms; Dysbindin; Dystrophin-Associated Proteins; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - genetics; Genes; Genetic aspects; Genetic engineering; Genetic regulation; Hyperkinesis - drug therapy; Hyperkinesis - etiology; Hyperkinesis - genetics; Kinases; Maze Learning - drug effects; Medical sciences; Medicine; Medicine & Public Health; Memory; Memory Disorders - drug therapy; Memory Disorders - etiology; Memory, Short-Term - drug effects; Memory, Short-Term - physiology; Mental health; Mice; Mice, Inbred DBA; Mice, Knockout; Motor Activity - drug effects; Motor Activity - genetics; Mutation; Neurosciences; original-article; Pharmacotherapy; Prefrontal cortex; Prefrontal Cortex - drug effects; Prefrontal Cortex - pathology; Prefrontal Cortex - physiopathology; Properties; Protein expression; Proteins; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychoses; Psychosis; Pyramidal Cells - drug effects; Reaction Time - drug effects; Reaction Time - genetics; Receptors, Dopamine D2 - metabolism; Schizophrenia; Schizophrenia - complications; Schizophrenia - pathology; Sensory Gating - drug effects; Sensory Gating - genetics; Stress, Psychological - physiopathology; United States; United States > US; Italy; schizophrenia; genes; working memory; dopamine; mice; prefrontal cortex; Cerebral cortex; Dopamine; Rodentia; Central nervous system; Schizophrenia; Cognition; Prefrontal cortex; Catecholamine; Genetic determinism; Encephalon; Psychosis; Vertebrata; Mammalia; Gene; Mouse; Animal; Neurotransmitter; Genetics; Behavior; Working memory
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/mp.2010.106

Dysbindin-1 regulates D2-receptor trafficking and is implicated in schizophrenia and related cognitive abnormalities, but whether this molecular effect mediates the clinical manifestations of the disorder is unknown. We explored in dysbindin-1-deficient mice (dys−/−) (1) schizophrenia-related behaviors, (2) molecular and electrophysiological changes in medial prefrontal cortex (mPFC) and (3) the dependence of these on D2-receptor stimulation. Dysbindin-1 disruption altered dopamine-related behaviors and impaired working memory under challenging/stressful conditions. Dys−/− pyramidal neurons in mPFC layers II/III were hyperexcitable at baseline but hypoexcitable following D2 stimulation. Dys−/− were also respectively more and less sensitive to D2 agonist- and antagonist-induced behavioral effects. Dys−/− had reduced expression of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) and CaMKKβ in mPFC. Chronic D2 agonist treatment reproduced these changes in protein expression, and some of the dys−/− behavioral effects. These results elucidate dysbindin's modulation of D2-related behavior, cortical activity and mPFC CaMK components, implicating cellular and molecular mechanisms of the association of dysbindin with psychosis.