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1、RoleofLeakyNeuronalRyanodineReceptorsinStress-InducedCognitiveDysfunctionXiaopingLiu,1MatthewJ.Betzenhauser,1SteveReiken,1AlbanoC.Meli,1WenjunXie,1Bi-XingChen,1OttavioArancio,2andAndrewR.Marks1,*1DepartmentofPhysiologyandCellularBiophysics,ClydeandHelenWuCenterforMolecularCardiology2Depa
2、rtmentofPathologyandCellBiology,TaubInstituteforResearchonAlzheimersDiseaseandtheAgingBrainColumbiaUniversityCollegeofPhysiciansandSurgeons,NewYork,NY10032,USA*Correspondence:arm42@columbia.eduhttp://dx.doi.org/10.1016/j.cell.2012.06.052SUMMARYleaseoccursviaryanodinereceptors(RyRs)andino
3、sitol(1,4,5)-trisphosphatereceptors(IP3Rs)ontheendoplasmicThetype2ryanodinereceptor/calciumreleasereticulum(ER)(Berridgeetal.,2003).Therearethreeisoformschannel(RyR2),requiredforexcitation-contractionofRyRinthebrain.RyR1andRyR2arebothexpressedinthecouplingintheheart,isabundantinthebrain.
4、hippocampus.RyR2expressionisupregulatedinrathippo-Chronicstressinducescatecholaminebiosynthesiscampusfollowingintensivetrainingtasks(Cavallaroetal.,andrelease,stimulatingb-adrenergicreceptorsand1997;Zhaoetal.,2000).RyR2knockdownimpairsperformanceofmiceinpassiveavoidancetests(Galeottietal
5、.,2008),whereasactivatingcAMPsignalingpathwaysinneurons.InRyR1knockdowndidnot(Galeottietal.,2008).amurinechronicrestraintstressmodel,neuronal2+CareleasedintothecytoplasmispumpedbackintotheERRyR2werephosphorylatedbyproteinkinaseAbytheERCa-ATPase(SERCA)orremovedfromthecellby(PKA),oxidized,
6、andnitrosylated,resultingindeple-theplasmamembraneCa-ATPase(PMCA)andNa+/Ca2+tionofthestabilizingsubunitcalstabin2(FKBP12.6)exchanger.AlteredCa2+homeostasiscontributestoneuronalfromthechannelcomplexandintracellularcalciumdegenerationandcelldeath(Mattson,2007)anddefectivepost-leak.Stress-i
7、nducedcognitivedysfunction,includ-synapticsignaling,presynapticcontrolofneurotransmitterre-ingdeficitsinlearningandmemory,andreducedlease,andlong-termsynapticplasticity(Berridge,1998;Fitzjohnlong-termpotentiation(LTP)atthehippocampalandCollingridge,2002).CA3-CA1connectionw
