Deletion of GSK3ß in D2R-expressing neurons reveals distinct roles for ß-arrestin signaling in antipsychotic and lithium action.
Proc Natl Acad Sci U S A
; 109(50): 20732-7, 2012 Dec 11.
Article
em En
| MEDLINE
| ID: mdl-23188793
ABSTRACT
Several studies in rodent models have shown that glycogen synthase kinase 3 ß (GSK3ß) plays an important role in the actions of antispychotics and mood stabilizers. Recently it was demonstrated that GSK3ß through a ß-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)/ß-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 GSK3ß in regulating DA- or lithium-sensitive behaviors, we generated conditional knockouts of GSK3ß, where GSK3ß 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 GSK3ß in D2 (D2GSK3ß(-/-)) but not D1 (D1GSK3ß(-/-)) neurons mimic antipsychotic action. However, haloperidol (HAL)-induced catalepsy was unchanged in either D2GSK3ß(-/-) or D1GSK3ß(-/-) mice compared with control mice. Interestingly, genetic stabilization of ß-catenin, a downstream target of GSK3ß, in D2 neurons did not affect any of the behaviors tested. Moreover, D2GSK3ß(-/-) or D1GSK3ß(-/-) mice showed similar responses to controls in the tail suspension test (TST) and dark-light emergence test, behaviors which were previously shown to be ß-arrestin2- and GSK3ß-dependent and sensitive to lithium treatment. Taken together these studies suggest that selective deletion of GSK3ß but not stabilization of ß-catenin in D2 neurons mimics antipsychotic action without affecting signaling pathways involved in catalepsy or certain mood-related behaviors.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Antipsicóticos
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Receptores de Dopamina D2
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Arrestinas
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Quinase 3 da Glicogênio Sintase
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Neurônios Dopaminérgicos
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Lítio
Limite:
Animals
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos