TY  - JOUR
A1  - Busse, Kathy
A1  - Strotmann, Rainer
A1  - Strecker, Karl
A1  - Wegner, Florian
A1  - Devanathan, Vasudharani
A1  - Gohla, Antje
A1  - Schöneberg, Torsten
A1  - Schwarz, Johannes
T1  - Adaptive Gene Regulation in the Striatum of RGS9-Deficient Mice
T2  - PLOS ONE
N2  - 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.
KW  - medium spiny neurons
KW  - long-term depression
KW  - dopa-induced dyskinesia
KW  - adenylyl cyclase
KW  - Parkinsons disease
KW  - synaptic plasticity
KW  - L-3,4-Dihydroxyphenylalanine-induced dyskinesia
KW  - ampa receptors
KW  - cholinergic interneurons
KW  - endocannabinoid release
Y1  - 2014
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/11704
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-117048
VL  - 9
IS  - 3
ER  -