Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for p-arrestin signaling in antipsychotic and lithium action

摘要

Several studies in rodent models have shown that glycogen synthase kinase 3 β (GSK3β) plays an important role in the actions of antispy-chotics and mood stabilizers. Recently it was demonstrated that GSK3p through a β-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 endophe-notypes of mania and depression in rodents. We have previously shown that atypical antipsychotics antagonize DA D2 receptor (D2R)/β-arrestin2 interactions more efficaciously than G-protein-de-pendent signaling, whereas typical antipsychotics inhibit both pathways with similar efficacy. To elucidate the site of action of GSK3β in regulating DA- or lithium-sensitive behaviors, we generated conditional knockouts of GSK3β, where GSK3β 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 GSK3p in D2 (D2GSK3β~(-/-)) but not D1 (D1GSK3β~(-/-)) neurons mimic antipsychotic action. However, haloperidol (HAL)-induced catalepsy was unchanged in either D2GSK3β~(-/-) or D1GSK3β~(-/-) mice compared with control mice. Interestingly, genetic stabilization of β-catenin, a downstream target of GSK3p, in D2 neurons did not affect any of the behaviors tested. Moreover, D2GSK3β~(-/-) or D1GSK3β~(-/-) mice showed similar responses to controls in the tail suspension test (TST) and dark-light emergence test, behaviors which were previously shown to be p-arrestin2- and GSK3β-dependent and sensitive to lithium treatment. Taken together these studies suggest that selective deletion of GSK3p but not stabilization of p-catenin in D2 neurons mimics antipsychotic action without affecting signaling pathways involved in catalepsy or certain mood-related behaviors.