Journal
MOLECULAR PSYCHIATRY
Volume 17, Issue 1, Pages 85-98Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/mp.2010.106
Keywords
dopamine; genes; mice; prefrontal cortex; schizophrenia; working memory
Funding
- NIH, National Institute of Mental Health
- NATIONAL INSTITUTE OF MENTAL HEALTH [ZICMH002901, ZICMH002906, ZIAMH002179, Z01MH002906] Funding Source: NIH RePORTER
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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 CaMKK beta 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. Molecular Psychiatry (2012) 17, 85-98; doi:10.1038/mp.2010.106; published online 19 October 2010
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