Protein Tyrosine Phosphatase PTP1B Is Involved in Hippocampal Synapse Formation and Learning 英文参考文献.docVIP

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Protein Tyrosine Phosphatase PTP1B Is Involved in Hippocampal Synapse Formation and Learning 英文参考文献.doc

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Protein Tyrosine Phosphatase PTP1B Is Involved in Hippocampal Synapse Formation and Learning 英文参考文献

ProteinTyrosinePhosphatasePTP1BIsInvolvedin HippocampalSynapseFormationandLearning FedericoFuentes1¤,DerekZimmer2,MaryblessAtienza2,JamieSchottenfeld2,IanPenkala2,TracyBale2, KendraK.Bence2*.,CarlosO.Arregui1*. 1Instituto de Investigaciones Biotecnolo′gicas, Universidad de San Mart?′n/CONICET, San Mart?′n, Buenos Aires, Argentina, 2Department of Animal Biology, School of VeterinaryMedicine,UniversityofPennsylvania,Philadelphia,Pennsylvania,UnitedStatesofAmerica Abstract ER-boundPTP1Bisexpressedinhippocampalneurons,andaccumulatesamongneuritecontacts.PTP1Bdephosphorylates ?-catenininN-cadherincomplexesensuringcell-celladhesion.HereweshowthatendogenousPTP1B,aswellasexpressed GFP-PTP1B,arepresentindendriticspinesofhippocampalneuronsinculture.GFP-PTP1Boverexpressiondoesnotaffect filopodial density or length. In contrast, impairment of PTP1B function or genetic PTP1B-deficiency leads to increased filopodia-like dendritic spines and a reduction in mushroom-like spines, while spine density is unaffected. These morphological alterations are accompanied by a disorganization of pre- and post-synapses, as judged by decreased clustering of synapsin-1 and PSD-95, and suggest a dynamic synaptic phenotype. Notably, levels of ?-catenin-Tyr-654 phosphorylationincreased,5-foldinthehippocampusofadultPTP1B2/2(KO)micecomparedtowildtype(WT)miceand thiswasaccompaniedbyareductionintheamountof?-cateninassociatedwithN-cadherin.TodeterminewhetherPTP1B- deficiencyalterslearningandmemory,wegeneratedmicelackingPTP1Binthehippocampusandcortex(PTP1Bfl/fl–Emx1- Cre).PTP1Bfl/fl–Emx1-CremicedisplayedimprovedperformanceintheBarnesmaze(decreasedtimetofindandentertarget hole),utilizedamoreefficientstrategy(cued),andhadbetterrecallcomparedtoWTcontrols.OurresultsimplicatePTP1Bin structural plasticity within the hippocampus, likely through modulation of N-cadherin function by ensuring dephosphorylationof?-cateninonTyr-654.DisruptionofhippocampalPTP1Bfunctionorexpressionleadstoelongation ofdendriticfilo