| First Author | Urs NM | Year | 2012 |
| Journal | Proc Natl Acad Sci U S A | Volume | 109 |
| Issue | 50 | Pages | 20732-7 |
| PubMed ID | 23188793 | Mgi Jnum | J:193121 |
| Mgi Id | MGI:5467677 | Doi | 10.1073/pnas.1215489109 |
| Citation | Urs NM, et al. (2012) Deletion of GSK3beta in D2R-expressing neurons reveals distinct roles for beta-arrestin signaling in antipsychotic and lithium action. Proc Natl Acad Sci U S A 109(50):20732-7 |
| abstractText | Several studies in rodent models have shown that glycogen synthase kinase 3 beta (GSK3beta) plays an important role in the actions of antispychotics and mood stabilizers. Recently it was demonstrated that GSK3beta through a beta-arrestin2/protein kinase B (PKB or Akt)/protein phosphatase 2A (PP2A) signaling complex regulates dopamine (DA)- and lithium-sensitive behaviors and is required to mediate endophenotypes of mania and depression in rodents. We have previously shown that atypical antipsychotics antagonize DA D2 receptor (D2R)/beta-arrestin2 interactions more efficaciously than G-protein-dependent signaling, whereas typical antipsychotics inhibit both pathways with similar efficacy. To elucidate the site of action of GSK3beta in regulating DA- or lithium-sensitive behaviors, we generated conditional knockouts of GSK3beta, where GSK3beta was deleted in either DA D1- or D2-receptor-expressing neurons. We analyzed these mice for behaviors commonly used to test antipsychotic efficacy or behaviors that are sensitive to lithium treatment. Mice with deletion of GSK3beta in D2 (D2GSK3beta(-/-)) but not D1 (D1GSK3beta(-/-)) neurons mimic antipsychotic action. However, haloperidol (HAL)-induced catalepsy was unchanged in either D2GSK3beta(-/-) or D1GSK3beta(-/-) mice compared with control mice. Interestingly, genetic stabilization of beta-catenin, a downstream target of GSK3beta, in D2 neurons did not affect any of the behaviors tested. Moreover, D2GSK3beta(-/-) or D1GSK3beta(-/-) mice showed similar responses to controls in the tail suspension test (TST) and dark-light emergence test, behaviors which were previously shown to be beta-arrestin2- and GSK3beta-dependent and sensitive to lithium treatment. Taken together these studies suggest that selective deletion of GSK3beta but not stabilization of beta-catenin in D2 neurons mimics antipsychotic action without affecting signaling pathways involved in catalepsy or certain mood-related behaviors. |
