title: Adaptive gene regulation in the Striatum of RGS9-deficient mice.
abstract: 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.
  
  
  CONCLUSIONS
  Changes in Ca2+ signaling that compensate for RGS9 loss-of-function can explain the normal locomotor activity in RGS9-deficient mice under unchallenged conditions.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, Medical Faculty, University of Leipzig, Leipzig, Germany; Institute of Biochemistry, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Kathy
authors.initials: K
authors.lastname: Busse
authors.affiliation: Institute of Biochemistry, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Strotmann
authors.affiliation: Department of Neurology, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Strecker
authors.affiliation: Department of Neurology, Medical Faculty, University of Leipzig, Leipzig, Germany; Translational Centre of Regenerative Medicine (TRM), University of Leipzig, Leipzig, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Wegner
authors.affiliation: Institute of Pharmacology and Toxicology, Eberhard Karls University of Tübingen, Tübinge, Germany.
authors.forename: Vasudharani
authors.initials: V
authors.lastname: Devanathan
authors.affiliation: Rudolf Virchow Centre of Experimental Biomedicine, Julius Maximilians University of Würzburg, Würzburg, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Gohla
authors.affiliation: Institute of Biochemistry, Medical Faculty, University of Leipzig, Leipzig, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Schöneberg
authors.affiliation: Department of Neurology, Medical Faculty, University of Leipzig, Leipzig, Germany; Translational Centre of Regenerative Medicine (TRM), University of Leipzig, Leipzig, Germany; Department of Neurology, Technical University of Munich, Munich, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D000242:Cyclic AMP / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation; D036881:Long-Term Synaptic Depression; D008297:Male; D051379:Mice; D017072:Neostriatum / Q000378:metabolism*; D009473:Neuronal Plasticity; D010766:Phosphorylation; D020710:RGS Proteins / Q000172:deficiency*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism
chemical_list: D020710:RGS Proteins; D017448:Receptors, Dopamine D2; C116925:regulator of g-protein signaling 9; D000242:Cyclic AMP