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.
Papaleo
F
F
Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, MD 20892, USA. francesco.papaleo@iit.it
Yang
F
F
Garcia
S
S
Chen
J
J
Lu
B
B
Crawley
J N
JN
Weinberger
D R
DR
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