Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 85-98 |
| Number of pages | 14 |
| Journal | Molecular psychiatry |
| Volume | 17 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2012 |
| Externally published | Yes |
Keywords
- dopamine
- genes
- mice
- prefrontal cortex
- schizophrenia
- working memory
ASJC Scopus subject areas
- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Molecular Biology