LTP.docx
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LTP.docx
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LTP
Long-termpotentiation
Long-termpotentiation(LTP)isapersistentincreaseinsynapticstrengthfollowinghigh-frequencystimulationofachemicalsynapse.StudiesofLTPareoftencarriedoutinslicesofthehippocampus,animportantorganforlearningandmemory.Insuchstudies,electricalrecordingsaremadefromcellsandplottedinagraphsuchasthisone.ThisgraphcomparestheresponsetostimuliinsynapsesthathaveundergoneLTPversussynapsesthathavenotundergoneLTP.SynapsesthathaveundergoneLTPtendtohavestrongerelectricalresponsestostimulithanothersynapses.Thetermlong-termpotentiationcomesfromthefactthatthisincreaseinsynapticstrength,orpotentiation,lastsaverylongtimecomparedtootherprocessesthataffectsynapticstrength.
Inneuroscience,long-termpotentiation(LTP)isapersistentstrengtheningofsynapsesbasedonrecentpatternsofactivity.Thesearepatternsofsynapticactivitythatproducealong-lastingincreaseinsignaltransmissionbetweentwoneurons.TheoppositeofLTPislong-termdepression(LTD)whichproducelong-lastingdecreaseinsynapticstrength.
Itisoneofseveralphenomenaunderlyingsynapticplasticity突触可塑性,theabilityofchemicalsynapsestochangetheirstrength.Asmemoriesarethoughttobeencodedbymodificationofsynapticstrength,LTPiswidelyconsideredoneofthemajorcellularmechanismsthatunderlieslearningandmemory.
LTPwasdiscoveredintherabbithippocampusbyTerjeLømoin1966andhasremainedapopularsubjectofresearchsince.ManymodernLTPstudiesseektobetterunderstanditsbasicbiology,whileothersaimtodrawacausallinkbetweenLTPandbehaviorallearning.Stillotherstrytodevelopmethods,pharmacologicorotherwise,ofenhancingLTPtoimprovelearningandmemory.LTPisalsoasubjectofclinicalresearch,forexample,intheareasofAlzheimer'sdiseaseandaddictionmedicine.
Contents
∙1History
o1.1Earlytheoriesoflearning
o1.2Discovery
o1.3Modelsandtheory
∙2Types
∙3Properties
o3.1Earlyphase
▪3.1.1Maintenance
▪3.1.2Expression
o3.2Latephase
▪3.2.1Induction
▪3.2.2Maintenance
▪3.2.3Expression
o3.3Retrogradesignaling
o3.4Synaptictagging
o3.5Modulation
∙4Relationshiptobehavioralmemory
o4.1Spatialmemory
o4.2Inhibitoryavoidance
∙5Clinicalsignificance
o5.1Alzheimer'sdisease
o5.2Drugaddiction
∙6Seealso
∙7References
∙8Furtherreading
∙9Externallinks
1.History
1.1Earlytheoriesoflearning
The19thcenturyneuroanatomistSantiagoRamónyCajalproposedthatmemoriesmightbestoredacrosssynapses,thejunctionsbetweenneuronsthatallowfortheircommunication.
Attheendofthe19thcentury,scientistsgenerallyrecognizedthatthenumberofneuronsintheadultbrain(roughly100billion)didnotincreasesignificantlywithage,givingneurobiologistsgoodreasontobelievethatmemoriesweregenerallynottheresultofnewneuronproduction.Withthisrealizationcametheneedtoexplainhowmemoriescouldformintheabsenceofnewneurons.
TheSpanishneuroanatomistSantiagoRamónyCajalwasamongthefirsttosuggestamechanismoflearningthatdidnotrequiretheformationofnewneurons.Inhis1894CroonianLecture,heproposedthatmemoriesmightinsteadbeformedbystrengtheningtheconnectionsbetweenexistingneuronstoimprovetheeffectivenessoftheircommunication.Hebbiantheory,introducedbyDonaldHebbin1949,echoedRamónyCajal'sideas,furtherproposingthatcellsmaygrownewconnectionsorundergometabolicchangesthatenhancetheirabilitytocommunicate.
Letusassumethatthepersistenceorrepetitionofareverberatoryactivity反射活动(or"trace")tendstoinducelastingcellularchangesthataddtoitsstability.WhenanaxonofcellAisnearenoughtoexciteacellBandrepeatedlyorpersistentlytakespartinfiringit,somegrowthprocessormetabolicchangetakesplaceinoneorbothcellssuchthatA'sefficiency,asoneofthecellsfiringB,isincreased.
Thoughthesetheoriesofmemoryformationarenowwellestablished,theywerefarsightedfortheirtime:
late19thandearly20thcenturyneuroscientistsandpsychologistswerenotequippedwiththeneurophysiologicaltechniquesnecessaryforelucidatingthebiologicalunderpinnings基础结构oflearninginanimals.Theseskillswouldnotcomeuntilthelaterhalfofthe20thcentury,ataboutthesametimeasthediscoveryoflong-termpotentiation.
1.2Discovery
颞叶
枕叶
额叶
颞叶
LTPwasfirstdiscoveredintherabbithippocampus.Inhumans,thehippocampusislocatedinthemedialtemporalloben内侧颞叶.
LTPwasfirstobservedbyTerjeLømoin1966intheOslo,Norway,laboratoryofPerAndersen.There,Lømoconductedaseriesofneurophysiologicalexperimentsonanesthetizedrabbitstoexploretheroleofthehippocampusinshort-termmemory.
Lømo'sexperimentsfocusedonconnections,orsynapses,fromtheperforantpathway穿通通路tothedentategyrus齿状回.Theseexperimentswerecarriedoutbystimulatingpresynapticfibersoftheperforantpathwayandrecordingresponsesfromacollectionofpostsynapticcellsofthedentategyrus.Asexpected,asinglepulseofelectricalstimulationtofibersoftheperforantpathwaycausedexcitatorypostsynapticpotentials(EPSPs)incellsofthedentategyrus.WhatLømounexpectedlyobservedwasthatthepostsynapticcells'responsetothesesingle-pulsestimulicouldbeenhancedforalongperiodoftimeifhefirstdeliveredahigh-frequencytrainofstimulitothepresynapticfibers.Whensuchatrainofstimuliwasapplied,subsequentsingle-pulsestimulielicited引出stronger,prolongedEPSPsinthepostsynapticcellpopulation.Thisphenomenon,wherebyahigh-frequencystimuluscouldproducealong-livedenhancementinthepostsynapticcells'responsetosubsequentsingle-pulsestimuli,wasinitiallycalled"long-lastingpotentiation".
TimothyBliss,whojoinedtheAndersenlaboratoryin1968,collaboratedwithLømoandin1973thetwopublishedthefirstcharacterizationoflong-lastingpotentiationintherabbithippocampus.BlissandTonyGardner-Medwinpublishedasimilarreportoflong-lastingpotentiationintheawakeanimalwhichappearedinthesameissueastheBlissandLømoreport.In1975,DouglasandGoddardproposed"long-termpotentiation"asanewnameforthephenomenonoflong-lastingpotentiation.Andersensuggestedthattheauthorschose"long-termpotentiation"perhapsbecauseofitseasilypronouncedacronym,"LTP".
1.3Modelsandtheory
Asynapseisrepeatedlystimulated.
Moredendriticreceptors.
Moreneurotransmitters.
Astrongerlinkbetweenneurons.
ThephysicalandbiologicalmechanismofLTPisstillnotunderstood,butsomesuccessfulmodelshavebeendeveloped.Studiesofdendriticspines树突棘头,protruding突出的structuresondendritesthatphysicallygrowandretractoverthecourseofminutesorhours,havesuggestedarelationshipbetweentheelectricalresistanceofthespineandtheeffectivesynapsestrength,duetotheirrelationshipwithintracellularcalciumtransients瞬变.MathematicalmodelssuchasBCMTheory,whichdependsalsoonintracellularcalciuminrelationtoNMDAreceptorvoltagegates,havebeendevelopedsincethe1980sandmodifythetraditionalaprioriHebbianlearningmodelwithbothbiologicalandexperimentaljustification.Stillothershaveproposedre-arrangingorsynchronizingtherelationshipbetweenreceptorregulation,LTP,andsynapticstrength.
2.Types
Sinceitsoriginaldiscoveryintherabbithippocampus,LTPhasbeenobservedinavarietyofotherneuralstructures,includingthecerebralcortex,cerebellum小脑,amygdala杏仁核,andmanyothers.RobertMalenka,aprominentLTPresearcher,hassuggestedthatLTPmayevenoccuratallexcitatorysynapsesinthemammalianbrain.
DifferentareasofthebrainexhibitdifferentformsofLTP.ThespecifictypeofLTPexhibitedbetweenneuronsdependsonanumberoffactors.OnesuchfactoristheageoftheorganismwhenLTPisobserved.Forexample,themolecularmechanismsofLTPintheimmaturehippocampusdifferfromthosemechanismsthatunderlieLTPoftheadulthippocampus.ThesignallingpathwaysusedbyaparticularcellalsocontributetothespecifictypeofLTPpresent.Forexample,sometypesofhippocampalLTPdependontheNMDAreceptor,othersmaydependuponthemetabotropicglutamatereceptor(mGluR),whilestillothersdependuponanothermoleculealtogether.ThevarietyofsignalingpathwaysthatcontributetoLTPandthewidedistributionofthesevariouspathwaysinthebrainarereasonsthatthetypeofLTPexhibitedbetweenneuronsdependsinpartupontheanatomiclocationinwhichLTPisobserved.Forexample,LTPintheSchaffercollateralpathwayofthehippocampusisNMDAreceptor-dependent,whereasLTPinthemossyfiberpathwayisNMDAreceptor-independent.
Thepre-andpostsynapticactivityrequiredtoinduceLTPareothercriteria标准bywhichLTPisclassified.Broadly,thisallowsclassificationofLTPintoHebbian,non-Hebbian,andanti-Hebbianmechanisms.BorrowingitsnamefromHebb'spostulate假说,summarizedbythemaximthat"cellsthatfiretogetherwiretogether,"HebbianLTPrequiressimultaneouspre-andpostsynapticdepolarizationforitsinduction.Non-HebbianLTPisatypeofLTPthatdoesnotrequiresuchsimultaneousdepolarizationofpre-andpostsynapticcells;anexampleofthisoccursinthemossyfiberhippocampalpathway.Aspecialcaseofnon-HebbianLTP,anti-HebbianLTPexplicitlyrequiressimultaneouspresynapticdepolarizationandrelativepostsynaptichyperpolarizationforitsinduction.
OwingtoitspredictableorganizationandreadilyinducibleLTP,theCA1hippocampushasbecometheprototypicalsiteofmammalianLTPstudy.Inparticular,NMDAreceptor-dependentLTPinthe
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