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Adaptive gene regulation in the striatum of RGS9-deficient mice

Background: RGS9-deficient mice show drug-induced dyskinesia but normal locomotor activity under unchallenged
conditions. Results: Genes related to Ca2+ signaling and their functions were regulated in RGS9-deficient mice. Conclusion: Changes in Ca2+ signaling that compensate for RGS9 loss-of-function can explain the normal locomotor activity in RGS9-deficient mice under unchallenged conditions. Significance: Identified signaling components may represent novel targets in antidyskinetic therapy. The long splice variant of the regulator of G-protein signaling 9 (RGS9-2) is enriched in striatal medium spiny neurons and dampens dopamine D2 receptor signaling. Lack of RGS9-2 can promote while its overexpression prevents drug-induced dyskinesia. Other animal models of drug-induced dyskinesia rather pointed towards overactivity of dopamine receptor-mediated signaling. To evaluate changes in signaling pathways mRNA expression levels were determined and compared in wild-type and RGS9- deficient mice. Unexpectedly, expression levels of dopamine receptors were unchanged in RGS9-deficient mice, while several genes related to Ca2+ signaling and long-term depression were differentially expressed when compared to wild type animals. Detailed investigations at the protein level revealed hyperphosphorylation of DARPP32 at Thr34 and of ERK1/2 in striata of RGS9-deficient mice. Whole cell patch clamp recordings showed that spontaneous synaptic events are increased (frequency and size) in RGS9-deficient mice while long-term depression is reduced in acute brain slices. These changes are compatible with a Ca2+-induced potentiation of dopamine receptor signaling which may contribute to the drug-induced dyskinesia in RGS9-deficient mice.:Introduction; Materials and methods; Results; Discussion

Identiferoai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:12479
Date January 2014
CreatorsBusse, Kathy, Strotmann, Rainer, Strecker, Karl, Wegner, Florian, Devanathan, Vasudharani, Gohla, Antje, Schöneberg, Torsten, Schwarz, Johannes
ContributorsUniversität Leipzig, Universität Tübingen, Universität Würzburg, Technische Universität München
PublisherPublic Library of Science
Source SetsHochschulschriftenserver (HSSS) der SLUB Dresden
LanguageEnglish
Detected LanguageEnglish
Typedoc-type:article, info:eu-repo/semantics/article, doc-type:Text
SourcePLOS One March, 24, 2014 doi: 10.1371/journal.pone.0092605
Rightsinfo:eu-repo/semantics/openAccess

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