Dysbindin-1 modulates prefrontal cortical activity and schizophrenia-like behaviors via dopamine/D2 pathways.
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.
Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, MD 20892, USA. francesco.papaleo@iit.it
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F
Papaleo
F
F
Yang
S
S
Garcia
J
J
Chen
B
B
Lu
J N
JN
Crawley
D R
DR
Weinberger
D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000661:Amphetamine / Q000009:adverse effects; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D006948:Hyperkinesis / Q000188:drug therapy / Q000209:etiology / Q000235:genetics; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D017397:Prefrontal Cortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D017966:Pyramidal Cells / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012559:Schizophrenia / Q000150:complications / Q000473:pathology*; D055139:Sensory Gating / Q000187:drug effects / Q000235:genetics; D013315:Stress, Psychological / Q000503:physiopathology
D002352:Carrier Proteins; D015259:Dopamine Agents; C498992:Dtnbp1 protein, mouse; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D017448:Receptors, Dopamine D2; D000661:Amphetamine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D004298:Dopamine