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

Publication ,  Journal Article
Urs, NM; Snyder, JC; Jacobsen, JPR; Peterson, SM; Caron, MG
Published in: Proc Natl Acad Sci U S A
December 11, 2012

Several studies in rodent models have shown that glycogen synthase kinase 3 β (GSK3β) plays an important role in the actions of antispychotics and mood stabilizers. Recently it was demonstrated that GSK3β 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 endophenotypes 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-dependent 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 GSK3β 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 GSK3β, 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 β-arrestin2- and GSK3β-dependent and sensitive to lithium treatment. Taken together these studies suggest that selective deletion of GSK3β but not stabilization of β-catenin in D2 neurons mimics antipsychotic action without affecting signaling pathways involved in catalepsy or certain mood-related behaviors.

Duke Scholars

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

December 11, 2012

Volume

109

Issue

50

Start / End Page

20732 / 20737

Location

United States

Related Subject Headings

  • beta-Arrestins
  • beta Catenin
  • Signal Transduction
  • Receptors, Dopamine D2
  • Quinolones
  • Piperazines
  • Motor Activity
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice, 129 Strain
 

Citation

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Urs, N. M., Snyder, J. C., Jacobsen, J. P. R., Peterson, S. M., & Caron, M. G. (2012). Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action. Proc Natl Acad Sci U S A, 109(50), 20732–20737. https://doi.org/10.1073/pnas.1215489109
Urs, Nikhil M., Joshua C. Snyder, Jacob P. R. Jacobsen, Sean M. Peterson, and Marc G. Caron. “Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action.Proc Natl Acad Sci U S A 109, no. 50 (December 11, 2012): 20732–37. https://doi.org/10.1073/pnas.1215489109.
Urs NM, Snyder JC, Jacobsen JPR, Peterson SM, Caron MG. Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action. Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20732–7.
Urs, Nikhil M., et al. “Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action.Proc Natl Acad Sci U S A, vol. 109, no. 50, Dec. 2012, pp. 20732–37. Pubmed, doi:10.1073/pnas.1215489109.
Urs NM, Snyder JC, Jacobsen JPR, Peterson SM, Caron MG. Deletion of GSK3β in D2R-expressing neurons reveals distinct roles for β-arrestin signaling in antipsychotic and lithium action. Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20732–20737.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

December 11, 2012

Volume

109

Issue

50

Start / End Page

20732 / 20737

Location

United States

Related Subject Headings

  • beta-Arrestins
  • beta Catenin
  • Signal Transduction
  • Receptors, Dopamine D2
  • Quinolones
  • Piperazines
  • Motor Activity
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice, 129 Strain