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Longtermpotentiation
FromWikipedia,thefreeencyclopedia

Inneuroscience,longtermpotentiation(LTP)isapersistent
strengtheningofsynapsesbasedonrecentpatternsofactivity.
Thesearepatternsofsynapticactivitythatproducealong
lastingincreaseinsignaltransmissionbetweentwoneurons.[2]
TheoppositeofLTPislongtermdepression,whichproducesa
longlastingdecreaseinsynapticstrength.
Itisoneofseveralphenomenaunderlyingsynapticplasticity,
theabilityofchemicalsynapsestochangetheirstrength.As
memoriesarethoughttobeencodedbymodificationof
synapticstrength,[3]LTPiswidelyconsideredoneofthemajor
cellularmechanismsthatunderlieslearningandmemory.[2][3]
LTPwasdiscoveredintherabbithippocampusbyTerjeLmo
in1966andhasremainedapopularsubjectofresearchsince.
ManymodernLTPstudiesseektobetterunderstanditsbasic
biology,whileothersaimtodrawacausallinkbetweenLTP
andbehaviorallearning.Stillotherstrytodevelopmethods,
pharmacologicorotherwise,ofenhancingLTPtoimprove
learningandmemory.LTPisalsoasubjectofclinicalresearch,
forexample,intheareasofAlzheimer'sdiseaseandaddiction
medicine.

Contents
1 History
1.1 Earlytheoriesoflearning
1.2 Discovery
1.3 Modelsandtheory
2 Types
3 Properties
3.1 Earlyphase
3.1.1 Maintenance
3.1.2 Expression
3.2 Latephase
3.2.1 Induction
3.2.2 Maintenance
3.2.3 Expression
3.3 Retrogradesignaling
3.4 Synaptictagging
3.5 Modulation
4 Relationshiptobehavioralmemory
4.1 Spatialmemory
4.2 Inhibitoryavoidance
5 Clinicalsignificance
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Longtermpotentiation(LTP)isapersistent
increaseinsynapticstrengthfollowinghigh
frequencystimulationofachemicalsynapse.
StudiesofLTPareoftencarriedoutinslicesofthe
hippocampus,animportantorganforlearningand
memory.Insuchstudies,electricalrecordingsare
madefromcellsandplottedinagraphsuchasthis
one.Thisgraphcomparestheresponsetostimuliin
synapsesthathaveundergoneLTPversussynapses
thathavenotundergoneLTP.Synapsesthathave
undergoneLTPtendtohavestrongerelectrical
responsestostimulithanothersynapses.Theterm
longtermpotentiationcomesfromthefactthatthis
increaseinsynapticstrength,orpotentiation,lastsa
verylongtimecomparedtootherprocessesthat
affectsynapticstrength. [1]

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5 Clinicalsignificance
5.1 Alzheimer'sdisease
5.2 Drugaddiction
6 Seealso
7 References
8 Furtherreading
9 Externallinks

History
Earlytheoriesoflearning
Attheendofthe19thcentury,scientistsgenerallyrecognizedthatthenumber
ofneuronsintheadultbrain(roughly100billion[4])didnotincrease
significantlywithage,givingneurobiologistsgoodreasontobelievethat
memoriesweregenerallynottheresultofnewneuronproduction.[5]Withthis
realizationcametheneedtoexplainhowmemoriescouldformintheabsence
ofnewneurons.
TheSpanishneuroanatomistSantiagoRamnyCajalwasamongthefirstto
suggestamechanismoflearningthatdidnotrequiretheformationofnew
neurons.Inhis1894CroonianLecture,heproposedthatmemoriesmight
insteadbeformedbystrengtheningtheconnectionsbetweenexistingneurons
toimprovetheeffectivenessoftheircommunication.[5]Hebbiantheory,
introducedbyDonaldHebbin1949,echoedRamnyCajal'sideas,further
proposingthatcellsmaygrownewconnectionsorundergometabolicchanges
thatenhancetheirabilitytocommunicate:
Letusassumethatthepersistenceorrepetitionofareverberatory
activity(or"trace")tendstoinducelastingcellularchangesthat
addtoitsstability....WhenanaxonofcellAisnearenoughto
exciteacellBandrepeatedlyorpersistentlytakespartinfiringit,
somegrowthprocessormetabolicchangetakesplaceinoneor
bothcellssuchthatA'sefficiency,asoneofthecellsfiringB,is
increased.[6]

The19thcenturyneuroanatomist
SantiagoRamnyCajalproposed
thatmemoriesmightbestored
acrosssynapses,thejunctions
betweenneuronsthatallowfor
theircommunication.

Thoughthesetheoriesofmemoryformationarenowwellestablished,theywerefarsightedfortheirtime:late19th
andearly20thcenturyneuroscientistsandpsychologistswerenotequippedwiththeneurophysiologicaltechniques
necessaryforelucidatingthebiologicalunderpinningsoflearninginanimals.Theseskillswouldnotcomeuntilthe
laterhalfofthe20thcentury,ataboutthesametimeasthediscoveryoflongtermpotentiation.

Discovery
LTPwasfirstobservedbyTerjeLmoin1966intheOslo,Norway,laboratoryofPerAndersen.[7][8]There,Lmo
conductedaseriesofneurophysiologicalexperimentsonanesthetizedrabbitstoexploretheroleofthe
hippocampusinshorttermmemory.
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Lmo'sexperimentsfocusedonconnections,orsynapses,fromtheperforant
pathwaytothedentategyrus.Theseexperimentswerecarriedoutby
stimulatingpresynapticfibersoftheperforantpathwayandrecording
responsesfromacollectionofpostsynapticcellsofthedentategyrus.As
expected,asinglepulseofelectricalstimulationtofibersoftheperforant
pathwaycausedexcitatorypostsynapticpotentials(EPSPs)incellsofthe
dentategyrus.WhatLmounexpectedlyobservedwasthatthepostsynaptic
cells'responsetothesesinglepulsestimulicouldbeenhancedforalong
periodoftimeifhefirstdeliveredahighfrequencytrainofstimulitothe
presynapticfibers.Whensuchatrainofstimuliwasapplied,subsequent
singlepulsestimulielicitedstronger,prolongedEPSPsinthepostsynapticcell
population.Thisphenomenon,wherebyahighfrequencystimuluscould
producealonglivedenhancementinthepostsynapticcells'responseto
subsequentsinglepulsestimuli,wasinitiallycalled"longlasting
potentiation".[9][10]
TimothyBliss,whojoinedtheAndersenlaboratoryin1968,[7]collaborated
withLmoandin1973thetwopublishedthefirstcharacterizationoflong
lastingpotentiationintherabbithippocampus.[9]BlissandTonyGardner
Medwinpublishedasimilarreportoflonglastingpotentiationintheawake
animalwhichappearedinthesameissueastheBlissandLmoreport.[10]In
1975,DouglasandGoddardproposed"longtermpotentiation"asanewname
forthephenomenonoflonglastingpotentiation.[11][12]Andersensuggested
thattheauthorschose"longtermpotentiation"perhapsbecauseofitseasily
pronouncedacronym,"LTP".[13]

LTPwasfirstdiscoveredinthe
rabbithippocampus.Inhumans,
thehippocampusislocatedinthe
medialtemporallobe.This
illustrationoftheundersideofthe
humanbrainshowsthe
hippocampushighlightedinred.
Thefrontallobeisatthetopof
theillustrationandtheoccipital
lobeisatthebottom.

Modelsandtheory
ThephysicalandbiologicalmechanismofLTPisstillnotunderstood,but
somesuccessfulmodelshavebeendeveloped.[1](http://www.scholarpedia.
org/article/Models_of_synaptic_plasticity)Studiesofdendriticspines,
protrudingstructuresondendritesthatphysicallygrowandretractoverthe
courseofminutesorhours,havesuggestedarelationshipbetweenthe
electricalresistanceofthespineandtheeffectivesynapsestrength,dueto
theirrelationshipwithintracellularcalciumtransients.Mathematical
modelssuchasBCMTheory,whichdependsalsoonintracellularcalcium
inrelationtoNMDAreceptorvoltagegates,havebeendevelopedsincethe
1980sandmodifythetraditionalaprioriHebbianlearningmodelwithboth
biologicalandexperimentaljustification.Stillothershaveproposedre
arrangingorsynchronizingtherelationshipbetweenreceptorregulation,
LTP,andsynapticstrength.[14]

Asynapseisrepeatedlystimulated.

Types
Sinceitsoriginaldiscoveryintherabbithippocampus,LTPhasbeenobservedinavarietyofotherneural
structures,includingthecerebralcortex,cerebellum,amygdala,[15]andmanyothers.RobertMalenka,aprominent
LTPresearcher,hassuggestedthatLTPmayevenoccuratallexcitatorysynapsesinthemammalianbrain.[16]

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DifferentareasofthebrainexhibitdifferentformsofLTP.Thespecifictype
ofLTPexhibitedbetweenneuronsdependsonanumberoffactors.One
suchfactoristheageoftheorganismwhenLTPisobserved.Forexample,
themolecularmechanismsofLTPintheimmaturehippocampusdiffer
fromthosemechanismsthatunderlieLTPoftheadulthippocampus.[17]The
signallingpathwaysusedbyaparticularcellalsocontributetothespecific
typeofLTPpresent.Forexample,sometypesofhippocampalLTPdepend
ontheNMDAreceptor,othersmaydependuponthemetabotropic
glutamatereceptor(mGluR),whilestillothersdependuponanother
moleculealtogether.[16]Thevarietyofsignalingpathwaysthatcontributeto
LTPandthewidedistributionofthesevariouspathwaysinthebrainare
reasonsthatthetypeofLTPexhibitedbetweenneuronsdependsinpart
upontheanatomiclocationinwhichLTPisobserved.Forexample,LTPin
theSchaffercollateralpathwayofthehippocampusisNMDAreceptor
dependent,whereasLTPinthemossyfiberpathwayisNMDAreceptor
independent.[18]
ThepreandpostsynapticactivityrequiredtoinduceLTPareothercriteria
bywhichLTPisclassified.Broadly,thisallowsclassificationofLTPinto
Hebbian,nonHebbian,andantiHebbianmechanisms.Borrowingitsname
fromHebb'spostulate,summarizedbythemaximthat"cellsthatfire
togetherwiretogether,"HebbianLTPrequiressimultaneouspreand
postsynapticdepolarizationforitsinduction.[19]NonHebbianLTPisa
typeofLTPthatdoesnotrequiresuchsimultaneousdepolarizationofpre
andpostsynapticcellsanexampleofthisoccursinthemossyfiber
hippocampalpathway.[20]AspecialcaseofnonHebbianLTP,anti
HebbianLTPexplicitlyrequiressimultaneouspresynapticdepolarization
andrelativepostsynaptichyperpolarizationforitsinduction.[21]
OwingtoitspredictableorganizationandreadilyinducibleLTP,theCA1
hippocampushasbecometheprototypicalsiteofmammalianLTPstudy.In
particular,NMDAreceptordependentLTPintheadultCA1hippocampus
isthemostwidelystudiedtypeofLTP,[16]andisthereforethefocusofthis
article.

Moredendriticreceptors.

Moreneurotransmitters.

Astrongerlinkbetweenneurons.

Properties
NMDAreceptordependentLTPexhibitsseveralproperties,includinginputspecificity,associativity,cooperativity,
andpersistence.
Inputspecificity
Onceinduced,LTPatonesynapsedoesnotspreadtoothersynapsesratherLTPisinputspecific.Longterm
potentiationisonlypropagatedtothosesynapsesaccordingtotherulesofassociativityandcooperativity.
However,theinputspecificityofLTPmaybeincompleteatshortdistances.Onemodeltoexplaintheinput
specificityofLTPwaspresentedbyFreyandMorrisin1997andiscalledthesynaptictaggingandcapture
hypothesis.
Associativity
Associativityreferstotheobservationthatwhenweakstimulationofasinglepathwayisinsufficientforthe
inductionofLTP,simultaneousstrongstimulationofanotherpathwaywillinduceLTPatbothpathways.
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Cooperativity
LTPcanbeinducedeitherbystrongtetanicstimulationofasinglepathwaytoasynapse,orcooperatively
viatheweakerstimulationofmany.Whenonepathwayintoasynapseisstimulatedweakly,itproduces
insufficientpostsynapticdepolarizationtoinduceLTP.Incontrast,whenweakstimuliareappliedtomany
pathwaysthatconvergeonasinglepatchofpostsynapticmembrane,theindividualpostsynaptic
depolarizationsgeneratedmaycollectivelydepolarizethepostsynapticcellenoughtoinduceLTP
cooperatively.Synaptictagging,discussedlater,maybeacommonmechanismunderlyingassociativityand
cooperativity.BruceMcNaughtonarguesthatanydifferencebetweenassociativityandcooperativityis
strictlysemantic.[22]
Persistence
LTPispersistent,lastingfromseveralminutestomanymonths,anditisthispersistencethatseparatesLTP
fromotherformsofsynapticplasticity.[23]

Earlyphase
Maintenance
WhileinductionentailsthetransientactivationofCaMKIIandPKC,
maintenanceofELTP(earlyformLTP)ischaracterizedbytheirpersistent
activation.Duringthisstage,PKMz(ProteinkinaseM)whichdoesnothave
dependenceoncalcium,becomeautonomouslyactive.Consequently,theyare
abletocarryoutthephosphorylationeventsthatunderlieELTP
expression.[25]
Expression
Phosphorylationisachemicalreactioninwhichasmallphosphategroupis
addedtoanothermoleculetochangethatmolecule'sactivity.Autonomously
activeCaMKIIandPKCusephosphorylationtocarryoutthetwomajor
mechanismsunderlyingtheexpressionofELTP.First,andmostimportantly,
theyphosphorylateexistingAMPAreceptorstoincreasetheiractivity.[16]
Second,theymediateormodulatetheinsertionofadditionalAMPAreceptors
intothepostsynapticmembrane.[16]Importantly,thedeliveryofAMPA
receptorstothesynapseduringELTPisindependentofproteinsynthesis.
ThisisachievedbyhavinganonsynapticpoolofAMPAreceptorsadjacentto
thepostsynapticmembrane.WhentheappropriateLTPinducingstimulus
arrives,nonsynapticAMPAreceptorsarerapidlytraffickedintothe
postsynapticmembraneundertheinfluenceofproteinkinases.[26]As
mentionedpreviously,AMPAreceptorsarethebrain'smostabundant
glutamatereceptorsandmediatethemajorityofitsexcitatoryactivity.By
increasingtheefficiencyandnumberofAMPAreceptorsatthesynapse,future
excitatorystimuligeneratelargerpostsynapticresponses.
WhiletheabovemodelofELTPdescribesentirelypostsynapticmechanisms
forinduction,maintenance,andexpression,anadditionalcomponentof
expressionmayoccurpresynaptically.[27]Onehypothesisofthispresynaptic
facilitationisthatpersistentCaMKIIactivityinthepostsynapticcellduringE
LTPmayleadtothesynthesisofa"retrogrademessenger",discussedlater.
Accordingtothishypothesis,thenewlysynthesizedmessengertravelsacross
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TheearlyphaseofLTP,one
modelofwhichisshownhere,is
independentofprotein
synthesis. [24]

Ca2+/calmodulindependent
proteinkinaseII(CaMKII)
appearstobeanimportant
mediatoroftheearly,protein
synthesisindependentphaseof
LTP.
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thesynapticcleftfromthepostsynaptictothepresynapticcell,leadingtoachainofeventsthatfacilitatethe
presynapticresponsetosubsequentstimuli.Sucheventsmayincludeanincreaseinneurotransmittervesicle
number,probabilityofvesiclerelease,orboth.Inadditiontotheretrogrademessengerunderlyingpresynaptic
expressioninearlyLTP,theretrogrademessengermayalsoplayaroleintheexpressionoflateLTP.

Latephase
LateLTP(LLTP)isthenaturalextensionofELTP.UnlikeELTP,whichis
independentofproteinsynthesis,LLTPrequiresgenetranscription[28]and
proteinsynthesis[29]inthepostsynapticcell.TwophasesofLLTPexist:the
firstdependsuponproteinsynthesis,whiletheseconddependsuponbothgene
transcriptionandproteinsynthesis.[24]Thesephasesareoccasionallycalled
LTP2andLTP3,respectively,withELTPreferredtoasLTP1underthis
nomenclature.
Induction
TheearlyandlatephasesofLTP
LateLTPisinducedbychangesingeneexpressionandproteinsynthesis
arethoughttocommunicatevia
broughtaboutbythepersistentactivationofproteinkinasesactivatedduring
theextracellularsignalregulated
ELTP,suchasMAPK.[24][25][30]Infact,MAPKspecificallytheextracellular
kinase(ERK). [24]
signalregulatedkinase(ERK)subfamilyofMAPKsmaybethemolecular
linkbetweenELTPandLLTP,sincemanysignalingcascadesinvolvedinE
LTP,includingCaMKIIandPKC,canconvergeonERK.[30]RecentresearchhasshownthattheinductionofL
LTPcandependoncoincidentmolecularevents,namelyPKAactivationandcalciuminflux,thatconvergeon
CRTC1(TORC1),apotenttranscriptionalcoactivatorforcAMPresponseelementbindingprotein(CREB).[31]
ThisrequirementforamolecularcoincidenceaccountsperfectlyfortheassociativenatureofLTP,and,
presumably,forthatoflearning.

Maintenance
Uponactivation,ERKmayphosphorylateanumberofcytoplasmicandnuclearmoleculesthatultimatelyresultin
theproteinsynthesisandmorphologicalchangesobservedinLLTP.[24]Thesecytoplasmicandnuclearmolecules
mayincludetranscriptionfactorssuchasCREB.[25]ERKmediatedchangesintranscriptionfactoractivitymay
triggerthesynthesisofproteinsthatunderliethemaintenanceofLLTP.Onesuchmoleculemaybeproteinkinase
M(PKM),apersistentlyactivekinasewhosesynthesisincreasesfollowingLTPinduction.[32][33]PKMisan
atypicalisoformofPKCthatlacksaregulatorysubunitandthusremainsconstitutivelyactive.[32]Unlikeother
kinasesthatmediateLTP,PKMisactivenotjustinthefirst30minutesfollowingLTPinductionrather,PKM
becomesarequirementforLTPmaintenanceonlyduringthelatephaseofLTP.[32]PKMthusappearsimportant
forthepersistenceofmemoryandwouldbeexpectedtobeimportantinthemaintenanceoflongtermmemory.
Indeed,administrationofaPKMinhibitorintothehippocampusoftheratresultsinretrogradeamnesiawith
intactshorttermmemoryPKMdoesnotplayaroleintheestablishmentofshorttermmemory.[33]PKMhas
recentlybeenshowntounderlieLLTPmaintenance[32][33]bydirectingthetraffickingandreorganizationof
proteinsinthesynapticscaffoldingthatunderlietheexpressionofLLTP.[32]Evenmorerecently,transgenicmice
lackingPKMdemonstratenormalLTP,questioningthenecessityofPKM[34]

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Thelongtermstabilizationofsynapticchangesisalsodeterminedbyaparallelincreaseofpreandpostsynaptic
structuressuchasaxonalbouton,dendriticspineandpostsynapticdensity.[35]Onthemolecularlevel,anincrease
ofthepostsynapticscaffoldingproteinsPSD95andHomer1chasbeenshowntocorrelatewiththestabilizationof
synapticenlargement.[35]
Expression
TheidentitiesofonlyafewproteinssynthesizedduringLLTPareknown.Regardlessoftheiridentities,itis
thoughtthattheycontributetotheincreaseindendriticspinenumber,surfacearea,andpostsynapticsensitivityto
neurotransmitterassociatedwithLLTPexpression.[24]Thelattermaybebroughtaboutinpartbytheenhanced
synthesisofAMPAreceptorsduringLLTP.[24]LateLTPisalsoassociatedwiththepresynapticsynthesisof
synaptotagminandanincreaseinsynapticvesiclenumber,suggestingthatLLTPinducesproteinsynthesisnot
onlyinpostsynapticcells,butinpresynapticcellsaswell.[24]Asmentionedpreviously,forpostsynapticLTP
inductiontoresultinpresynapticproteinsynthesis,theremustbecommunicationfromthepostsynaptictothe
presynapticcell.Thismayoccurviathesynthesisofaretrogrademessenger,discussedlater.
Eveninstudiesrestrictedtopostsynapticevents,investigatorshavenotdeterminedthelocationoftheprotein
synthesisthatunderliesLLTP.Specifically,itisunclearwhetherproteinsynthesistakesplaceinthepostsynaptic
cellbodyorinitsdendrites.[30]Despitehavingobservedribosomes(themajorcomponentsoftheproteinsynthesis
machinery)indendritesasearlyasthe1960s,prevailingwisdomwasthatthecellbodywasthepredominantsite
ofproteinsynthesisinneurons.[30]Thisreasoningwasnotseriouslychallengeduntilthe1980s,wheninvestigators
reportedobservingproteinsynthesisindendriteswhoseconnectiontotheircellbodyhadbeensevered.[30]More
recently,investigatorshavedemonstratedthatthistypeoflocalproteinsynthesisisnecessaryforsometypesof
LTP.[36][37]
Onereasonforthepopularityofthelocalproteinsynthesishypothesisisthatitprovidesapossiblemechanismfor
thespecificityassociatedwithLTP.[30]Specifically,ifindeedlocalproteinsynthesisunderliesLLTP,only
dendriticspinesreceivingLTPinducingstimuliwillundergoLTPthepotentiationwillnotbepropagatedto
adjacentsynapses.Bycontrast,globalproteinsynthesisthatoccursinthecellbodyrequiresthatproteinsbe
shippedouttoeveryareaofthecell,includingsynapsesthathavenotreceivedLTPinducingstimuli.Whereas
localproteinsynthesisprovidesamechanismforspecificity,globalproteinsynthesiswouldseemtodirectly
compromiseit.However,asdiscussedlater,thesynaptictagginghypothesissuccessfullyreconcilesglobalprotein
synthesis,synapsespecificity,andassociativity.

Retrogradesignaling
Retrogradesignalingisahypothesisthatattemptstoexplainthat,whileLTPisinducedandexpressed
postsynaptically,someevidencesuggeststhatitisexpressedpresynapticallyaswell.[16][27][38]Thehypothesisgets
itsnamebecausenormalsynaptictransmissionisdirectionalandproceedsfromthepresynaptictothepostsynaptic
cell.Forinductiontooccurpostsynapticallyandbepartiallyexpressedpresynaptically,amessagemusttravelfrom
thepostsynapticcelltothepresynapticcellinaretrograde(reverse)direction.Oncethere,themessagepresumably
initiatesacascadeofeventsthatleadstoapresynapticcomponentofexpression,suchastheincreasedprobability
ofneurotransmittervesiclerelease.[39]
Retrogradesignalingiscurrentlyacontentioussubjectassomeinvestigatorsdonotbelievethepresynapticcell
contributesatalltotheexpressionofLTP.[16]Evenamongproponentsofthehypothesisthereiscontroversyover
theidentityofthemessenger.Earlythoughtsfocusedonnitricoxide,whilemostrecentevidencepointstocell
adhesionproteins.[16]
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Synaptictagging
Beforethelocalproteinsynthesishypothesisgainedsignificantsupport,therewasgeneralagreementthatthe
proteinsynthesisunderlyingLLTPoccurredinthecellbody.Further,therewasthoughtthattheproductsofthis
synthesiswereshippedcellwideinanonspecificmanner.Itthusbecamenecessarytoexplainhowprotein
synthesiscouldoccurinthecellbodywithoutcompromisingLTP'sinputspecificity.Thesynaptictagging
hypothesisattemptstosolvethecell'sdifficultproblemofsynthesizingproteinsinthecellbodybutensuringthey
onlyreachsynapsesthathavereceivedLTPinducingstimuli.
Thesynaptictagginghypothesisproposesthata"synaptictag"issynthesizedatsynapsesthathavereceivedLTP
inducingstimuli,andthatthissynaptictagmayservetocaptureplasticityrelatedproteinsshippedcellwidefrom
thecellbody.[40]StudiesofLTPinthemarinesnailAplysiacalifornicahaveimplicatedsynaptictaggingasa
mechanismfortheinputspecificityofLTP.[41][42]Thereissomeevidencethatgiventwowidelyseparated
synapses,anLTPinducingstimulusatonesynapsedrivesseveralsignalingcascades(describedpreviously)that
initiatesgeneexpressioninthecellnucleus.Atthesamesynapse(butnottheunstimulatedsynapse),localprotein
synthesiscreatesashortlived(lessthanthreehours)synaptictag.Theproductsofgeneexpressionareshipped
globallythroughoutthecell,butareonlycapturedbysynapsesthatexpressthesynaptictag.Thusonlythesynapse
receivingLTPinducingstimuliispotentiated,demonstratingLTP'sinputspecificity.
ThesynaptictaghypothesismayalsoaccountforLTP'sassociativityandcooperativity.Associativity(see
Properties)isobservedwhenonesynapseisexcitedwithLTPinducingstimulationwhileaseparatesynapseis
onlyweaklystimulated.WhereasonemightexpectonlythestronglystimulatedsynapsetoundergoLTP(since
weakstimulationaloneisinsufficienttoinduceLTPateithersynapse),bothsynapseswillinfactundergoLTP.
Whileweakstimuliareunabletoinduceproteinsynthesisinthecellbody,theymaypromptthesynthesisofa
synaptictag.Simultaneousstrongstimulationofaseparatepathway,capableofinducingcellbodyprotein
synthesis,thenmayprompttheproductionofplasticityrelatedproteins,whichareshippedcellwide.Withboth
synapsesexpressingthesynaptictag,bothwouldcapturetheproteinproductsresultingintheexpressionofLTPin
boththestronglystimulatedandweaklystimulatedpathways.
CooperativityisobservedwhentwosynapsesareactivatedbyweakstimuliincapableofinducingLTPwhen
stimulatedindividually.Butuponsimultaneousweakstimulation,bothsynapsesundergoLTPinacooperative
fashion.Synaptictaggingdoesnotexplainhowmultipleweakstimulicanresultinacollectivestimulussufficient
toinduceLTP(thisisexplainedbythepostsynapticsummationofEPSPsdescribedpreviously).Rather,synaptic
taggingexplainstheabilityofweaklystimulatedsynapses,noneofwhicharecapableofindependentlygenerating
LTP,toreceivetheproductsofproteinsynthesisinitiatedcollectively.Asbefore,thismaybeaccomplished
throughthesynthesisofalocalsynaptictagfollowingweaksynapticstimulation.

Modulation
Asdescribedpreviously,themoleculesthat
underlieLTPcanbeclassifiedasmediators
ormodulators.AmediatorofLTPisa
molecule,suchastheNMDAreceptoror
calcium,whosepresenceandactivityis
necessaryforgeneratingLTPundernearly
allconditions.Bycontrast,amodulatorisa
moleculethatcanalterLTPbutisnot
essentialforitsgenerationorexpression.[16]

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ProposedmodulatorsofLTP[25]
Modulator
Target
Adrenergicreceptor

cAMP,MAPKamplification

Nitricoxidesynthase

Guanylylcyclase,PKG,NMDAR

Dopaminereceptor

cAMP,MAPKamplification

Metabotropicglutamatereceptor PKC,MAPKamplification

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Inadditiontothesignalingpathwaysdescribedabove,hippocampalLTPmaybealteredbyavarietyof
modulators.Forexample,thesteroidhormoneestradiolmayenhanceLTPbydrivingCREBphosphorylationand
subsequentdendriticspinegrowth.[43]Additionally,adrenergicreceptoragonistssuchasnorepinephrinemay
altertheproteinsynthesisdependentlatephaseofLTP.[44]Nitricoxidesynthaseactivitymayalsoresultinthe
subsequentactivationofguanylylcyclaseandPKG.[45]Similarly,activationofdopaminereceptorsmayenhance
LTPthroughthecAMP/PKAsignalingpathway.[46][47]

Relationshiptobehavioralmemory
Whilethelongtermpotentiationofsynapsesincellcultureseemstoprovideanelegantsubstrateforlearningand
memory,thecontributionofLTPtobehaviorallearningthatis,learningatthelevelofthewholeorganism
cannotsimplybeextrapolatedfrominvitrostudies.Forthisreason,considerableefforthasbeendedicatedto
establishingwhetherLTPisarequirementforlearningandmemoryinlivinganimals.Becauseofthis,LTPalso
playsacrucialroleinfearprocessing.

Spatialmemory
In1986,RichardMorrisprovidedsomeofthefirstevidencethatLTP
wasindeedrequiredfortheformationofmemoriesinvivo.[48]He
testedthespatialmemoryofratsbypharmacologicallymodifyingtheir
hippocampus,abrainstructurewhoseroleinspatiallearningiswell
established.RatsweretrainedontheMorriswatermaze,aspatial
memorytaskinwhichratsswiminapoolofmurkywateruntilthey
locatetheplatformhiddenbeneathitssurface.Duringthisexercise,
normalratsareexpectedtoassociatethelocationofthehidden
platformwithsalientcuesplacedatspecificpositionsaroundthe
circumferenceofthemaze.Aftertraining,onegroupofratshadtheir
hippocampibathedintheNMDAreceptorblockerAPV,whilethe
othergroupservedasthecontrol.Bothgroupswerethensubjectedto
TheMorriswatermazetaskhasbeenused
thewatermazespatialmemorytask.Ratsinthecontrolgroupwere
todemonstratethenecessityofNMDA
abletolocatetheplatformandescapefromthepool,whilethe
receptorsinestablishingspatialmemories.
performanceofAPVtreatedratswassignificantlyimpaired.
Moreover,whenslicesofthehippocampusweretakenfromboth
groups,LTPwaseasilyinducedincontrols,butcouldnotbeinducedinthebrainsofAPVtreatedrats.This
providedearlyevidencethattheNMDAreceptorandbyextension,LTPwasrequiredforatleastsometypes
oflearningandmemory.
Similarly,SusumuTonegawademonstratedin1996thattheCA1areaofthehippocampusiscrucialtothe
formationofspatialmemoriesinlivingmice.[49]Socalledplacecellslocatedinthisregionbecomeactiveonly
whentheratisinaparticularlocationcalledaplacefieldintheenvironment.Sincetheseplacefieldsare
distributedthroughouttheenvironment,oneinterpretationisthatgroupsofplacecellsformmapsinthe
hippocampus.Theaccuracyofthesemapsdetermineshowwellaratlearnsaboutitsenvironmentandthushow
wellitcannavigateit.TonegawafoundthatbyimpairingtheNMDAreceptor,specificallybygenetically
removingtheNR1subunitintheCA1region,theplacefieldsgeneratedweresubstantiallylessspecificthanthose
ofcontrols.Thatis,miceproducedfaultyspatialmapswhentheirNMDAreceptorswereimpaired.Asexpected,
thesemiceperformedverypoorlyonspatialtaskscomparedtocontrols,furthersupportingtheroleofLTPin
spatiallearning.

Inhibitoryavoidance
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In2006,JonathanWhitlockandcolleaguesreportedonaseriesofexperimentsthatprovidedperhapsthestrongest
evidenceofLTP'sroleinbehavioralmemory,arguingthattoconcludethatLTPunderliesbehaviorallearning,the
twoprocessesmustbothmimicandoccludeoneanother.[50]Employinganinhibitoryavoidancelearning
paradigm,researcherstrainedratsinatwochamberedapparatuswithlightanddarkchambers,thelatterbeing
fittedwithadevicethatdeliveredafootshocktotheratuponentry.AnanalysisofCA1hippocampalsynapses
revealedthatinhibitoryavoidancetraininginducedinvivoAMPAreceptorphosphorylationofthesametypeas
thatseeninLTPinvitrothatis,inhibitoryavoidancetrainingmimickedLTP.Inaddition,synapsespotentiated
duringtrainingcouldnotbefurtherpotentiatedbyexperimentalmanipulationsthatwouldhaveotherwiseinduced
LTPthatis,inhibitoryavoidancetrainingoccludedLTP.Inaresponsetothearticle,TimothyBlissandcolleagues
remarkedthattheseandrelatedexperiments"substantiallyadvancethecaseforLTPasaneuralmechanismfor
memory."[51]

Clinicalsignificance
TheroleofLTPindiseaseislessclearthanitsroleinbasicmechanismsofsynapticplasticity.However,
alterationsinLTPmaycontributetoanumberofneurologicaldiseases,includingdepression,Parkinson'sdisease,
epilepsy,andneuropathicpain.[52]ImpairedLTPmayalsohavearoleinAlzheimer'sdiseaseanddrugaddiction.

Alzheimer'sdisease
LTPhasreceivedmuchattentionamongthosewhostudyAlzheimer'sdisease(AD),a
neurodegenerativediseasethatcausesmarkedcognitivedeclineanddementia.Much
ofthisdeteriorationoccursinassociationwithdegenerativechangesinthe
hippocampusandothermedialtemporallobestructures.Becauseofthehippocampus'
wellestablishedroleinLTP,somehavesuggestedthatthecognitivedeclineseenin
individualswithADmayresultfromimpairedLTP.
Ina2003reviewoftheliterature,Rowanetal.proposedonemodelforhowLTP
mightbeaffectedinAD.[53]ADappearstoresult,atleastinpart,frommisprocessing
ofamyloidprecursorprotein(APP).Theresultofthisabnormalprocessingisthe
accumulationoffragmentsofthisprotein,calledamyloid(A).Aexistsinboth
solubleandfibrillarforms.MisprocessingofAPPresultsintheaccumulationof
solubleAthat,accordingtoRowan'shypothesis,impairshippocampalLTPandmay
leadtothecognitivedeclineseenearlyinAD.
ADmayalsoimpairLTPthroughmechanismsdistinctfromA.Forexample,one
studydemonstratedthattheenzymePKMaccumulatesinneurofibrillarytangles,
whichareapathologicmarkerofAD.PKMisanenzymewithcriticalimportancein
themaintenanceoflateLTP.[54]

Drugaddiction

Misprocessingof
amyloidprecursor
protein(APP)in
Alzheimer'sdisease
disruptsLTPandis
thoughttoleadtoearly
cognitivedeclinein
individualswiththe
disease. [53]

ResearchinthefieldofaddictionmedicinehasalsorecentlyturneditsfocustoLTP,owingtothehypothesisthat
drugaddictionrepresentsapowerfulformoflearningandmemory.[55]Addictionisacomplexneurobehavioral
phenomenoninvolvingvariouspartsofthebrain,suchastheventraltegmentalarea(VTA)andnucleusaccumbens
(NAc).StudieshavedemonstratedthatVTAandNAcsynapsesarecapableofundergoingLTP[55]andthatthis
LTPmayberesponsibleforthebehaviorsthatcharacterizeaddiction.[56]

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Seealso
Synapticplasticity
Neuroplasticity
Longtermdepression
Longtermmemory
Actinremodelingofneurons
Transcranialdirectcurrentstimulation

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Furtherreading
Bliss,TCollingridge,GMorris,R(2004).Longtermpotentiation:enhancingneurosciencefor30years.
Oxford:OxfordUniversityPress.ISBN0198530307.

Externallinks
Researchersprovidefirstevidenceforlearningmechanism(http://www.physorg.com/news75650360.html),
aPhysOrg.comreporton2006studybyBearandcolleagues.
ShortvideodocumentaryabouttheDoogiemice.(http://news.bbc.co.uk/olmedia/435000/video/_435883_pal
lab9_vi.ram)(RealPlayerformat)
"SmartMouse",aQuantumABCTVepisodeabouttheDoogiemice.(http://www.abc.net.au/quantum/storie
s/s103200.htm)
LongTermPotentiation(https://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=LongTerm+Poten
tiation)attheUSNationalLibraryofMedicineMedicalSubjectHeadings(MeSH)
Retrievedfrom"https://en.wikipedia.org/w/index.php?title=Longterm_potentiation&oldid=723393084"

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