On the Mechanism of Synaptic Depression Induced by CaMKIIN, an Endogenous Inhibitor of CaMKII 英文参考文献.docVIP

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On the Mechanism of Synaptic Depression Induced by CaMKIIN, an Endogenous Inhibitor of CaMKII 英文参考文献.doc

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On the Mechanism of Synaptic Depression Induced by CaMKIIN, an Endogenous Inhibitor of CaMKII 英文参考文献

OntheMechanismofSynapticDepressionInducedby CaMKIIN,anEndogenousInhibitorofCaMKII CamiloGouet1,BelenAburto1,2,CeciliaVergara1,MagdalenaSanhueza1,2* 1DepartmentofBiology,FacultyofSciences,UniversityofChile,Santiago,Chile,2MillenniumInstituteforCellDynamicsandBiotechnology,UniversityofChile,Santiago, Chile Abstract Activity-dependentsynapticplasticityunderlies,atleastinpart,learningandmemoryprocesses.NMDAreceptor(NMDAR)- dependent long-term potentiation (LTP) is a major synaptic plasticity model. During LTP induction, Ca /calmodulin- 2+ dependent protein kinase II (CaMKII) is activated, autophosphorylated and persistently translocated to the postsynaptic density,whereitbindstotheNMDAR.Ifanyofthesestepsisinhibited,LTPisdisrupted.TheendogenousCaMKIIinhibitor proteins CaMKIINa,b are rapidly upregulated in specific brain regions after learning. We recently showed that transient application of peptides derived from CaMKIINa (CN peptides) persistently depresses synaptic strength and reverses LTP saturation,asitallowsfurtherLTPinductioninpreviouslysaturatedpathways.ThetreatmentdisruptsbasalCaMKII-NMDAR interactionanddecreasesboundCaMKIIfractioninspines.TounravelCaMKIINfunctionandtofurtherunderstandCaMKII roleinsynapticstrengthmaintenance,herewemoredeeplyinvestigatedthemechanismofsynapticdepressioninducedby CN peptides (CN-depression) in rat hippocampal slices. We showed that CN-depression does not require glutamatergic 2+ synapticactivityorCa signaling,thusdiscardingunspecifictriggeringofactivity-dependentlong-termdepression(LTD)in slices. Moreover, occlusion experiments revealed that CN-depression and NMDAR-LTD have different expression mechanisms. We showed that CN-depression does not involve complex metabolic pathways including protein synthesis orproteasome-mediateddegradation.Remarkably,CN-depressioncannotberesolvedinneonaterats,forwhichCaMKIIis mostlycytosolicandvirtuallyabsentatthepostsynapticdensities.Overall,ourresultssupportadirecteffectofCNpeptides on synapti