{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:42:03Z","timestamp":1790253723778,"version":"4.1.0"},"reference-count":60,"publisher":"National Academy of Sciences","issue":"50","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,12,11]]},"abstract":"<jats:p>\n                    Several studies in rodent models have shown that glycogen synthase kinase 3 \u03b2 (GSK3\u03b2) plays an important role in the actions of antispychotics and mood stabilizers. Recently it was demonstrated that GSK3\u03b2 through a \u03b2-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)\/\u03b2-arrestin2 interactions more efficaciously than G-protein\u2013dependent signaling, whereas typical antipsychotics inhibit both pathways with similar efficacy. To elucidate the site of action of GSK3\u03b2 in regulating DA- or lithium-sensitive behaviors, we generated conditional knockouts of GSK3\u03b2, where GSK3\u03b2 was deleted in either DA D1- or D2-receptor\u2013expressing 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 GSK3\u03b2 in D2 (D2GSK3\u03b2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) but not D1 (D1GSK3\u03b2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) neurons mimic antipsychotic action. However, haloperidol (HAL)-induced catalepsy was unchanged in either D2GSK3\u03b2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    or D1GSK3\u03b2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice compared with control mice. Interestingly, genetic stabilization of \u03b2-catenin, a downstream target of GSK3\u03b2, in D2 neurons did not affect any of the behaviors tested. Moreover, D2GSK3\u03b2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    or D1GSK3\u03b2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice showed similar responses to controls in the tail suspension test (TST) and dark\u2013light emergence test, behaviors which were previously shown to be \u03b2-arrestin2- and GSK3\u03b2-dependent and sensitive to lithium treatment. Taken together these studies suggest that selective deletion of GSK3\u03b2 but not stabilization of \u03b2-catenin in D2 neurons mimics antipsychotic action without affecting signaling pathways involved in catalepsy or certain mood-related behaviors.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1215489109","type":"journal-article","created":{"date-parts":[[2012,11,28]],"date-time":"2012-11-28T20:13:04Z","timestamp":1354133584000},"page":"20732-20737","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":87,"title":["Deletion of GSK3\u03b2 in D2R-expressing neurons reveals distinct roles for \u03b2-arrestin signaling in antipsychotic and lithium action"],"prefix":"10.1073","volume":"109","author":[{"given":"Nikhil M.","family":"Urs","sequence":"first","affiliation":[{"name":"Departments of aCell Biology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua C.","family":"Snyder","sequence":"additional","affiliation":[{"name":"Departments of aCell Biology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob P. 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