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ARoleforNeuronalpiRNAsintheEpigeneticControlofMemory-RelatedSynapticPlasticityPriyamvadaRajasethupathy,1IgorAntonov,1RobertSheridan,4SebastianFrey,5ChrisSander,4ThomasTuschl,5,*andEricR.Kandel1,2,3,*1DepartmentofNeuroscience2HowardHughesMedicalInstitute3KavliInstituteforBrainSciencesColumbiaUniversity,NewYork,NY10032,USA4ComputationalandSystemsBiologyCenter,MemorialSloan-KetteringCancerCenter,NewYork,NY10065,USA5LaboratoryofRNAMolecularBiology,HowardHughesMedicalInstitute,TheRockefellerUniversity,1230YorkAvenue,NewYork,NY10065,USA*Correspondence:ttuschl@rockefeller.edu(T.T.),erk5@columbia.edu(E.R.K.)DOI10.1016/j.cell.2012.02.057SUMMARY2004).(2)AutoregulatoryandpositivefeedbackloopswithinproteinnetworkscanallowpersistentenzymaticactivityofSmallRNA-mediatedgeneregulationduringdevel-proteinsornewlysynthesizedproteintotaketheplaceofexist-opmentcauseslong-lastingchangesincellularphe-ingproteinmachinerywithoutlossinstateandfunction(Lisman,notypes.TodeterminewhethersmallRNAsofthe1985;HayerandBhalla,2005;Songetal.,2007;Serranoetal.,adultbraincanregulatememorystorage,aprocess2008).(3)Andperhapsmosttantalizingisthepossibilitythatthatrequiresstableandlong-lastingchangesintheepigeneticmechanismssuchasDNAmethylationcanalterfunctionalstateofneurons,wegeneratedsmallgeneexpressionandthustheintrinsicpropertiesofneuronsinalong-termfashion,perhapsontheorderofyears(Crick,RNAlibrariesfromtheAplysiaCNS.Intheselibraries,1984;DavisandSquire,1984;Weaveretal.,2004;Milleretal.,wediscoveredanunexpectedlyabundantexpres-2010;Fengetal.,2010).sionofa28nucleotidesizedclassofpiRNAsinbrain,SmallregulatorynoncodingRNAscancauselong-lastingwhichhadbeenthoughttobegermlinespecific.changesincellularphenotypesduringdevelopment,throughThesepiRNAshaveuniquebiogenesispatterns,theirinvolvementbothinautoregulatoryfeedbackloops(Hobert,predominantnuclearlocalization,androbustsensi-2008;Rybaketal.,2008;Kroletal.,2010a)andinthetran-tivitytoserotonin,amodulatorytransmitterthatisscripti
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