Patterned Neuroprotection in the Inpp4awbl Mutant Mouse Cerebellum Correlates with the Expression of Eaat4 英文参考文献.docVIP

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Patterned Neuroprotection in the Inpp4awbl Mutant Mouse Cerebellum Correlates with the Expression of Eaat4 英文参考文献.doc

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Patterned Neuroprotection in the Inpp4awbl Mutant Mouse Cerebellum Correlates with the Expression of Eaat4 英文参考文献

PatternedNeuroprotectionintheInpp4awbl Mutant MouseCerebellumCorrelateswiththeExpressionof Eaat4 AndrewJ.Sachs1,SamuelA.David1,NeenaB.Haider1,2*,ArneM.Nystuen1* 1Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America, 2Department of OphthalmologyandVisualSciences,UniversityofNebraskaMedicalCenter,Omaha,Nebraska,UnitedStatesofAmerica Abstract Theweeblemutantmousehasaframeshiftmutationininositolpolyphosphate4-phosphatasetypeI(Inpp4a).Thephenotype ischaracterizedbyanearlyonsetcerebellarataxiaandneurodegeneration,especiallyapparentinthePurkinjecells.Purkinje celllossisacommonpathologicalfindinginmanyhumanandmouseataxicdisorders.HereweshowthatintheInpp4awbl mutant,Purkinjecellsarelostinaspecifictemporalandspatialpattern.Lossoccursearlyinpostnataldevelopment;however, priortotheappearanceofclimbingfibersinthedevelopingmolecularlayer,themutanthasanormalcomplementofPurkinje cellsandtheyareproperlypositioned.Degenerationandreactivegliosisarepresentatpostnatalday5andprogressrapidlyin adefinedpatternofpatches;however,Inpp4aisexpresseduniformlyacrossPurkinjecells.Inlatestagemutants,patchesof surviving Purkinje cells appear remarkably normal with the exception that the climbing fibers have been excessively eliminated.SurvivingPurkinjecellsexpressEaat4,aglutamatetransporterthatisdifferentiallyexpressedinsubsetsofPurkinje cellsduringdevelopmentandintoadultstages.PriortoPurkinjecellloss,reactivegliosisanddendriticatrophycanbeseenin Eaat4negativestripes.OurdatasuggestthatPurkinjecelllossintheInpp4awbl mutantisduetoglutamateexcitotoxicity initiatedbytheclimbingfiber,andthatEaat4mayexertaprotectiveeffect. Citation: Sachs AJ, David SA, Haider NB, Nystuen AM (2009) Patterned Neuroprotection in the Inpp4awbl Mutant Mouse Cerebellum Correlates with the ExpressionofEaat4.PLoSONE4(12):e8270.doi:10.1371/journal.pone.0008270 Editor:KatrinaGwinn,BaylorCollegeofMedicine,UnitedStatesofAmerica ReceivedJuly22,2009;A