Dynamic Changes in Neurexins Alternative Splicing Role of Rho-Associated Protein Kinases and Relevance to Memory Formation 英文参考文献.docVIP

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Dynamic Changes in Neurexins Alternative Splicing Role of Rho-Associated Protein Kinases and Relevance to Memory Formation 英文参考文献.doc

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Dynamic Changes in Neurexins Alternative Splicing Role of Rho-Associated Protein Kinases and Relevance to Memory Formation 英文参考文献

DynamicChangesinNeurexins’AlternativeSplicing: RoleofRho-AssociatedProteinKinasesandRelevanceto MemoryFormation GabrielaRozic1,ZiporaLupowitz1,YaelPiontkewitz2,NavaZisapel1* 1DepartmentofNeurobiology,GeorgeS.WiseFacultyofLifeSciences,Tel-AvivUniversity,Tel-Aviv,Israel,2DepartmentofPsychology,FacultyofSocialSciences,Tel- AvivUniversity,Tel-Aviv,Israel Abstract The threeneurexinsgenes (NRXN1/2/3)encode polymorphic synaptic membraneproteins that areinvolved in cognitive functioning. Neurexins’ selectivity of function is presumably conferred through differential use of 2 promoters and 5 alternativesplicingsites(SS#1/2/3/4/5).Inday-oldratbrainneuronsgrowninculture,activation(depolarization)induces reversible,calciumdependent,repressionofNRXN2aSS#3insert.TheeffectsofdepolarizationonNRXN1/2/3asplicingand biochemicalpathwaysmediatingthemwerefurtherstudiedintheseneurons.NRXN1/2/3asplicinginthecourseofmemory formationinvivowasalsoexplored,usingfearconditioningparadigminratsinwhichtheanimalsweretrainedtoassociate anaversivestimulus(electricalshock)withaneutralcontext(atone),resultingintheexpressionoffearresponsestothe neutralcontext. Intheculturedneuronsdepolarizationinduced,besideNRXN2aSS#3,repressionofSS#3andSS# 4exons inNRXN3abutnotNRXN1a.Therepressionsweremediatedbythecalcium/proteinkinaseC/Rho-associatedproteinkinase (ROCK)pathway.FearconditioninginducedsignificantandtransientrepressionsoftheNRXN1/2/3aSS#4exonsintherat hippocampus. ROCK inhibition prior to training attenuated the behavioral fear response, the NRXN1/2/3a splicing repressionsandsubsequentrecoveryandthelevelsofexcitatory(PSD95)andinhibitory(gephyrin)synapticproteinsinthe hippocampus. No such effects were observed in the prefrontal cortex. Significant correlations existed between the fear responseandhippocampalNRXN3aandNRXN2aSS#4insertsaswellasPSD95proteinlevels.HippocampalNRXN1aSS#4 insert and gephyrin levels did not correlate with the behavioral response but were negatively correlated with each other. T