Developmental Profile of the Aberrant Dopamine D2 Receptor Response in Striatal Cholinergic Interneurons in DYT1 Dystonia 英文参考文献.docVIP

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Developmental Profile of the Aberrant Dopamine D2 Receptor Response in Striatal Cholinergic Interneurons in DYT1 Dystonia 英文参考文献.doc

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Developmental Profile of the Aberrant Dopamine D2 Receptor Response in Striatal Cholinergic Interneurons in DYT1 Dystonia 英文参考文献

DevelopmentalProfileoftheAberrantDopamineD2 ReceptorResponseinStriatalCholinergicInterneuronsin DYT1Dystonia GiuseppeSciamanna1,2,AnnalisaTassone1,2,GiuseppinaMartella1,GeorgiaMandolesi2 ,Francesca Puglisi1,2,DarioCuomo1,GraziaMadeo1,GiuliaPonterio1,DavidGeorgeStandaert3,PaolaBonsi2, AntonioPisani1,2 * 1Department of Neuroscience, University ‘‘Tor Vergata’’, Rome, Italy, 2Laboratory of Neurophysiology and Plasticity, Fondazione Santa Lucia I.R.C.C.S., Rome, Italy, 3DepartmentofNeurology,CenterforNeurodegenerationandExperimentalTherapeutics,UniversityofAlabamaatBirmingham,Birmingham,Alabama,UnitedStatesof America Abstract Background:DYT1dystonia,asevereformofgeneticallydeterminedhumandystonia,exhibitsreducedpenetranceamong carriersandbeginsusuallyduringadolescence.Thereasonsforsuchagedependenceandvariabilityremainunclear. Methods and Results: We characterized the alterations in D2 dopamine receptor (D2R) signalling in striatal cholinergic interneuronsatdifferentagesinmiceoverexpressinghumanmutanttorsinA(hMT).Anabnormalexcitatoryresponsetothe D2Ragonistquinpirolewasrecordedatpostnatalday14,consistingofamembranedepolarizationcoupledtoanincrease inspikingfrequency,andpersistedunchangedat3and9monthsinhMTmice,comparedtomiceexpressingwild-type humantorsinAandnon-transgenicmice.ThisresponsewasblockedbytheD2RantagonistsulpirideanddependeduponG- proteins, as it was prevented by intrapipette GDP-b-S. Patch-clamp recordings from dissociated interneurons revealed a significant increase in the Cav2.2-mediated current fraction at all ages examined. Consistently, chelation of intracellular calciumabolishedtheparadoxicalresponsetoquinpirole.Finally,nogrossmorphologicalchangeswereobservedduring development. Conclusions: These results suggest that an imbalanced striatal dopaminergic/cholinergic signaling occurs early in DYT1 dystoniaandpersistsalongdevelopment,representingasusceptibilityfactorforsymptomgeneration. Citation:SciamannaG,TassoneA,MartellaG,MandolesiG,PuglisiF,etal.(2011)D