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.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa.de:bsz:15-qucosa-144141 |
| Date | 27 May 2014 |
| Creators | Busse, Kathy, Strotmann, Rainer, Strecker, Karl, Wegner, Florian, Devanathan, Vasudharani, Gohla, Antje, Schöneberg, Torsten, Schwarz, Johannes |
| Contributors | Universität Leipzig, Medizinische Fakultät, Universität Leipzig, Medizinische Fakultät, Universität Leipzig, Translationszentrum für Regenerative Medizin, Universität Tübingen, Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universität Würzburg, Rudolf-Virchow-Zentrum für Experimentelle Biomedizin, Technische Universität München, Neurologische Klinik und Poliklinik, Public Library of Science, |
| Publisher | Universitätsbibliothek Leipzig |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | doc-type:article |
| Format | application/pdf |
| Source | PLOS One March, 24, 2014 doi: 10.1371/journal.pone.0092605 |
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