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Annu.Rev. Psychol. 1996.47:173–203Copyright© 1996by AnnualReviewsInc. All rightsreserved

LONG-TERM POTENTIATION ANDLEARNING

JoeL. Martinez, Jr.andBrian E. Derrick

TheUniversity of Texas, San Antonio, Texas78249-0662

KEY WORDS: memory, hippocampus,synaptic plasticity, Hebb, neural networks

ABSTRACT

Long-term potentiation (LTP), a relatively long-lived increase in synapticstrength, remains the most popular model for the cellular process that mayunderlieinformationstoragewithinneuralsystems.Thestrongestargumentsfora role of LTP in memory aretheoretical and involve Hebb’s Postulate,Marr’stheory of hippocampal function, andneural network theory. Considering LTPresearch asa whole, few studies have addressed the essential question: IsLTPa process involved in learning and memory? The present manuscript reviewsresearchthatattemptstolinkLTPwith learningandmemory,focusingonstudiesutilizingelectrophysiological, pharmacological, andmolecular biologicalmeth-odologies.Most evidence firmly supportsa role for LTP in learning memory.However,anunequivocal experimental demonstration of acontribution of LTPto memory is hampered by our lack of knowledge of the biological basis ofmemory andof the waysin which memories are represented in ensembles ofneurons, the existence of a variety of cellular forms of LTP, and the likelyresistanceof distributedmemorystorestodegradationbytreatmentsthatincom-pletely disrupt LTP.

CONTENTSINTRODUCTION..................................................................................................................... 174

Assertion 1: MemoryIs Storedin Networks ofNeurons..................................................... 174Assertion 2: MemoryIs StoredthroughChangesin Synaptic Function............................. 174Assertion 3: LTPCould Operate in Networks of Neuronsto StoreMemory ina

Manner Similar to That in Hebb’s Postulate ............................................................. 175LTP Is Specific to TetanizedInputs..................................................................................... 176LTP Is Associative.................................... ......................................................................... 176

LTP Lasts aLong TimeasDoesLong-Term Memory........................................................ 178CELLULAR MECHANISMS OFLTP INDUCTION............................................................. 179

NMDA-Receptor-DependentLTP and AssociativeLTP..................................................... 179Opioid-Receptor-DependentLTPand AssociativeLTP ..................................................... 179

ELECTROPHYSIOLOGICAL APPROACHESTO RELATING LTP TO LEARNING ...... 181DoesLearningProduceLTP-like Changes?....................................................................... 181Doesthe Induction of LTPInfluenceLearning?................................................................. 185

PHARMACOLOGICAL APPROACHESRELATING LTP TO LEARNING ...................... 187DoesLearningof a Spatial Task InvolveHippocampal Opioid Systems?.......................... 191

KNOCKOUT MUTANTS,LTP, AND HIPPOCAMPALLY DEPENDENT LEARNING ... 192CONCLUSION ......................................................................................................................... 198

INTRODUCTION

All neurobiologistswould agreethat information is acquired,stored,andre-trieved bythe brain;memoryis a thingin a placein abrain. Unfortunately,wedo not understandcompletelyhow anybrainencodesmemoryasa biologicalentity. However, the brain’s cellular architectureprovidesclues.All brainsconsistof individual cellular units or neurons.Most neuronshavethe sameparts:a dendritictree,cell-body,axon,andsynapticbuttons.The majority ofneuronscommunicatewith eachotheracrossa synapticspacevia neurotrans-mittersandneuromodulators.In mammalianbrains,billions of neuronsinter-connectin vastnetworksvia evenmorebill ionsof synapses.This fact leadstoour firstassertionaboutmemory.

Assertion 1: MemoryIs Stored in Networksof Neurons

The brain accomplishes all of its remarkableactivity through networksofneurons.A single neuronis unlikely to encodea specific memory; rather,ensembles of neurons participate in maintaining a representation thatserves as a memory.Such ensemblesrequire dynamic interactionsamongneuronsand an ability to modify theseinteractions.This implies a needforuse-dependentchangesin synapticfunction andleadsto thesecondassertionaboutmemory.

Assertion 2: MemoryIs Stored throughChangesin SynapticFunction

Hebb(1949) increasedour understandingof how networksof neuronsmightstoreinformation with the provocativetheory that memoriesarerepresentedby reverberatingassemblies of neurons.Hebb recognizedthat a memorysorepresentedcannotreverberateforeverandthatsomealterationin thenetworkmustoccurto provideintegrity both to maketheassemblya permanenttraceandto makeit morelikely that the tracecould be reconstructedasa remem-brance.Thus,our secondassertionis that,becauseneuronscommunicatewith

174 MARTINEZ & DERRICK

eachotheronly at synapses,the activity of the assemblyor network is mosteasily (perhapsonly) alteredby changesin synapticfunction. Hebb (1949)formalizedthis ideain what is knownasHebb’s Postulate:“When anaxonofcell A is nearenoughto excitecell B andrepeatedlyor persistently takespartin firing it, somegrowth processor metabolic changetakesplacein one orboth cells suchthatA’s efficiency,asoneof thecells firing B, is increased.”Hebb’s Postulateis very closeto a modern-daydefinition of long-termpoten-tiation (LTP) and leadsto two more assertionsaboutwhy LTP could be amechanismof memorystorage.

Assertion 3: LTPCould Operatein Networksof Neurons toStoreMemoryin a Manner Similar to Thatin Hebb’s Postulate

Bliss & Lomo (1973) first reportedthat tetanicstimulation of the perforantpath in anesthetizedrabbits increasedthe slopeof the population excitatorypost-synaptic potential (EPSP)recordedextracellularlyin the dentategyrusandreducedthe thresholdfor eliciting a populationactionpotential(popula-tion spike).TheydefinedLTP aspotentiation that lastedlongerthan30 min,althoughtheyobservedLTP for severalhours.LaterstudiesshowedthatLTPrecordedin animalswith permanentindwelling electrodeslastedfrom weeksto months(Barnes1979).Moreover,LTP is foundin manyareasof neocortex(Bear & Kirkwood1993).

A line of reasoningthat led to the conclusionthat LTP is a mechanismofmemoryis derivedfrom theoreticalstudieson neuralnetworks.Marr (1971)describedan associativenetwork in areaCA3 of the hippocampus in whichdistributed patternsof activity were imposedon principal cells; the tracebecameestablishedasaresultof strengtheningsynapticconnections.Sincethework of Hebb(1949)andthe discoveryof LTP (Bliss & Lomo 1973),thesetheoreticalconnectionsamongneuronsthat strengthenasa resultof activityarereferred to as HebbSynapses.

Synapticstrengthening asdescribedby theHebbRulecouldincreasewith-out bound. Becausesuch a Hebbianmechanismwould lead to saturation,anti-Hebbprocessesweresuggested(Stent1973,Sejnowski1977).Recentlytherehasbeena surgeof interestin long-termdepression(LTD) both as amemorymechanism(homosynapticor associativeLTD) andasa processthatnormalizessynaptic weights in networks(homosynaptic and heterosynapticLTD; cf Morris 1989b, Linden & Conner 1995, Roll s 1989, Derrick &Martinez 1995).

The use of the Hebb Rule in a distributed memory systemcan lead toefficient storageof a numberof representationswithin thesamenetwork(alsocalledcorrelationmatrix memories;seeMcNaughton& Morris 1987),whichcan be regeneratedwith partial input(pattern completion). The notion ofcorrelationmatrix memoriesresolvesthe seemingparadoxof how specific

LTP AND LEARNING 175

memoriesor representationsare stored in nonspecific(distributed) stores.Further,anyparticularpartof thenetworkis not essentialfor patterncomple-tion; theperformanceof theentirenetworkdeterioratesgraduallyasmoreandmore units are damagedor eliminated.This feature,referredto as gracefuldegradation,is a naturalby-productof distributedmemorystores(Rolls 1989,Rumelhart& McClelland 1986) and is characteristicof neuralsystems(seeRumelhart& McClelland1986).Moreover,storageof memorywithin distrib-uted systemsrestson the ability of neuronsto form synapse-specificaltera-tionsin synapticstrength.Thuswe cometo our third assertionaboutmemory.If memory is stored in networksof neuronsand if network efficiencyismediatedby persistentactivity (Hebb’s Postulate),thenLTP inducedby per-sistentstimulationof anafferentpathwayis at leastonelikely mechanismbywhich thebrain storesinformation.

Togetherthesethreeassertionsprovidea powerful rationalefor the claimthat LTP is a substrateof memory.However,becauseno onehasisolated amemorytrace,LTP cannotbestudiedin a knownmemorynetwork.Thustheevidencereviewedin this paperis correlationaland inferential. Before weconsiderthe evidence,we discussthreeother similarities betweenLTP andlearningthat someconsidersupportthenotion thatLTP is a memorymecha-nism: LTP is specific to tetanizedinputs,it is associative,andit lastsa longtime. In our view, theseargumentsunfortunately focuseddiscussion on simi-larities betweenclassicalconditioning and LTP that, to date,remainmerelysimilarities.

LTP Is Specificto Tetanized Inputs

Sincethe time of Pavlov (1927),conditioned reflexeshavebeenthoughttoinvolve specificneuralpathways.In fact,simpleneuralreflexesmaybeincor-poratedinto conditioned reflexes.LTP is specific in this way in that onlytetanizedafferentsshowpotentiation, so-calledhomosynaptic LTP. Unfortu-nately,the ideaof specificity of tetanizedafferentshasbecomecloudedwithreportsthat LTP induction might involve gases,suchasnitrousoxide (NO),that readily diffuse into adjacentneurons(O’Dell et al 1991, Schuman&Madison 1991). Also, evidencesuggeststhat maintenanceof LTP involvesretrogrademessengersthat alsomay affect neighboringneurons(Bonhoefferet al 1989).This lack of specificityhasadvantagesovera strict HebbRule inthatdiffusealterationsin presynapticelements(referredto asvolumelearning)may permit the storageof the temporalorder of inputs (Montague& Se-jnowski 1994).

LTP Is Associative

Another interesting propertyof LTP, which led someresearchersto suggestthat it is a memorymechanism,is associativity. If weak non-LTP-inducing


stimulation in oneafferentis pairedwith strongLTP-inducingstimulation inanotherafferentto thesamecell population, thentheweaklystimulatedaffer-entexhibitsLTP (Levy & Steward1979,McNaughtonet al 1978).Theprop-erty of associativity is reminiscentof classicalconditioning, in which aneutralCSis associatedwith a strongUCSto induceconditioning(Makintosh1974).As theargument goes,becauseneuralafferentsin associativeLTP actin awaysimilar to neural activityin classicalconditioning, and because the mechanismof associative LTP is the sameas in LTP, at least in N-methyl-D-aspartate(NMDA) receptor–dependentsystemsLTP is a memory mechanism. Thisproposition hasbeenroundly criticized.The critics’ view (Gallistel 1995) isthat the temporalconstraintsof associative LTP are dissimilar to thoseofclassicalconditioning.In addition,thenecessaryorderingof CSandUCSareabsentin associativeLTP, and a mechanismas simple as associative LTPcannotaccountfor thebehavioralcomplexity observedin classicalcondition-ing.

Todaymost researcherswould agreethat associativeLTP is not classicalconditioning (Diamond& Rose1994).LTP does,however,bearcomparisonto a psychological exampleof learning.Associative LTP, describedby Hebb(1949) as the simultaneous activity of sensoryafferents,is more similar tosensorypreconditioning thanclassicalconditioning (Mackintosh1974).Sen-sorypreconditioning is theassociation of two sensorystimuli—for example,atoneanda light—by repeatedpairing.Thecomparisonof associativeLTP andsensorypreconditioning is straightforward:Thestimuli neednot bepresentedin aparticular order,nordoes aUCS needbepresent,asin classicalcondition-ing. However,temporalcontiguity for the presentationof the two stimuli isrequired(Kelso & Brown 1986, Mackintosh1974). In our view, it is moreproperto compareassociativeLTP to sensorypreconditioning thanto classicalconditioning. An interestingobservationin this regardis that hippocampallesionsappear toabolishsensorypreconditioning (Port et al1987).

From a behavioralpoint of view, LTP is moreanalogousto sensitization,and LTD is more analogousto habituation—both forms of nonassociativelearning—thaneitheris to classicalconditioning.Habituationmaybedefinedauthoritatively asa “responsedecrementasa resultof repeatedstimulation”(Harriscited in Thompson& Spencer1966). Sensitization maybedefinedasaresponse increment as a result of repeated (usually strong) stimulation(Thompson& Spencer1966). LTP and LTD are responseincrementsanddecrementsthat resultfrom repeatedstimulation(Bliss & Lomo 1973,Dudek& Bear 1993). Most researcherswould not agreethat LTP is analogoustosensitization becauseinduction of LTP requiresthat a thresholdnumberoffibershaveto besimultaneouslyactive(McNaughtonet al 1978).Cooperativ-ity could involve associativeinteractionswithin the postsynaptic target or


amongpresynapticfibers(whereasHebbianassociativity impliesa postsynap-tic associative effectof multiple fibers).

Thecomparison of LTDand habituationhasnot been made, but aparamet-ric analysisof habituationis available(Thompson& Spencer1966).Habitu-ation andsensitization were recognizedquite early to be separateprocesses,and dishabituation was viewed as sensitization inducedsimultaneouslywithhabituation (Thompson & Spencer 1966). An analogous contemporary co-nundrum is whetherdepotentiation representsthe addition of separateandoppositely signed processes, or the cellular reversal of LTP (Bear &Malenka 1994). While the comparisonsof LTP and LTD to psychologicalphenomenawill undoubtedly continue, it seemsthatsimple isomorphismsdonotexist.

LTP Lasts a Long Timeas DoesLong-TermMemory

The lasting natureof LTP has beenusedas an argumentboth for (Barnes1979)andagainst(Gallistel1995)LTP asa memorymechanism; the latter issupportedby the fact thatLTP doesnot lasta lifetime, asdo somememories(Squire1987).However,anynumberof propertiesof networks—forexample,reactivation(Hebb1949)—may extendthe biological integrity of a memory.Further,most studiescharacterizingLTP longevity observedLTP at hippo-campalsites. Becausethe hippocampusis viewed as having a temporallyrestrictedrole in memoryin both animalsand humans(Barnes1988,Zola-Morgan & Squire 1993), there is no a priori reasonto expectpermanentchangeswithin the hippocampus. Thus, longevity comparisonsbetweenhip-pocampalLTP andlong-termmemoriesarenot meaningful.Memory is not aunitaryphenomenon, andmemorysystemslikely includeanatomicallydistinctstructuresandevenperhapsdistinct neuralmechanisms(Schacter& Tulving1994).Perhapssynapticplasticitywithin otherpartsof thebrain—inneocorti-cal regions,for example—lasts longerthan hippocampal LTP.

In our view thefindings discussedto this point offer compelling reasonstoconsiderLTP (andLTD) likely biological mechanismsof memory.Thisexten-siveprologuewasrequiredbecausetheevidencesupportingsuchan interpre-tation is not convincing to some(Keith & Rudy 1990, Gallistel 1995) andbecauseeachsetof studiessupportingthis view carriesinterpretationaldiffi -culties.We now turn to a discussionof theevidence.First, we briefly list theknown cellular mechanismsfor LTP; for moreextensivereviewsof cellularmechanisms,seeBliss & Collingridge(1993),Bramham(1992),and Johnstonet al (1992).Thenwe discusselectrophysiological correlationsbetweenLTPandlearning,inductionof LTP andits effecton learning,thepharmacologicalpropertiesof learningand LTP, and new studiesthat attemptto determinesimultaneouslythe geneticbasisof LTP and learning.


CELLULAR MECHANISMS OF LTPINDUCTION

Severaldifferent forms of LTP havebeendescribed(Bliss & Collingridge1993). In the hippocampus,two major forms of LTP are NMDA receptor-dependent(Collingridgeet al 1983)or opioid receptor-dependent(Bramham1992).Each is discussed.

NMDA-Receptor-DependentLTP andAssociativeLTP

NMDA is avoltage-dependentglutamatereceptorsubtype.ForLTP induction,theNMDA receptormustbe activatedby theneurotransmitter glutamateandsimultaneously theremust be sufficient depolarization ofthe postsynapticmembraneto relieve a Mg2+ block in the NMDA-associatedion channel,which allows theentry of Ca2+ into the postsynaptic terminal.Ca2+ activatesany numberof Ca2+-sensitive secondmessengerprocesses.BecauseNMDAreceptorsare sensitive tobothpresynaptictransmitterreleaseandpostsynapticdepolarization,they act asHebbiancoincidencedetectors.This propertycanexplaincooperativityandassociativity throughtemporalandspatialsumma-tion. Thus,activatedNMDA receptorsat synapsesthatareproximal to activesites of depolarizationmay be depolarizedsufficiently to relieve the Mg2+

block and initiate the cascadeof eventsthat leadsto LTP induction. Thiscascademay occureventhoughthe activity of that particularsynapsealonewasnot sufficient to induceLTP. Thus,NMDA receptorscanaccountfor theassociationof two separateafferentprojectionsto thesamecell, onestronglyand the otherweakly active(Kelso & Brown 1986,Levy & Steward1979),and for the cooperativerequirement thata thresholdnumber of fibers beactive.RecentlyBashiret al (1993)suggestedthat otherglutamatereceptors,particularlythe metabotropic subtype,maycontributeto theinductionof LTP.

The maintenanceof NMDA-receptor-dependentLTP is less well under-stood.In a contemporaryreview a distinction wassuggestedbetweenshort-term potentiation (STP),which decaysin aboutonehour, followed by threestagesof LTP (LTP1–3) requiring, respectively(a) protein kinaseactivationandproteinphosphorylation, (b) proteinsynthesis from existing mRNAs,and(c) geneexpression(Bliss & Collingridge 1993). Behavioralapproachestolearning suggested that these samecellular processesareinvolved intheestab-lishmentof long-termmemory(Brinton 1991).

Opioid-Receptor-DependentLTP and AssociativeLTP

Although lesswell known and lesscompletelystudied (Bramham1991a,b;Breindl et al 1994;Derrick et al 1991;Ishihara1990;Martin 1983),this formof LTP is the predominantform of plasticity within extrinsicafferentsto thehippocampal formation (mossy-fiber CA3, lateral-perforant-pathdentategyrus,lateral-perforant-pathCA3) andis presentin moreafferentprojections


to the hippocampalformation than is NMDA-receptor-dependentLTP (me-dial-perforant-path dentate gyrus, medial-perforant-pathCA3). Thus if thehippocampusis importantin memoryformation,asmuchdatasuggests, thenopioid-receptor-dependentLTP and its relationshipto NMDA-receptor-de-pendentLTP need tobe understood.

LTP induction in the mossy-fiber CA3 and lateral-perforant-pathCA3pathwaysdependson theactivationof µ-opioid receptors(Derrick et al 1992,but seeWeisskopf et al 1993) and induction in the perforant-pathdentatepathwaydependson δ-opioid receptors(Bramhamet al 1991a,1992).There-fore, more than one formof opioid-receptor-dependentLTP exists in thehippocampus.We refer to thedifferent formsasLTPµ (mossy-fiberCA3 andlateral-perforant-path CA3)and LTPδ (lateral-perforant-path dentate).

Thetime coursesof NMDA-receptor-dependentandLTPµ differ in that theformer reachesits maximum almost immediately and can begin to decay,whereasthe latter takesapproximatelyan hour to reachits maximum andshowsno decay(Derrick & Martinez1989).Thesedifferent time coursesofaugmentationanddecayarerelevantto our understandingof theoperationofthese formsof LTP inneural networks.

Associativeopioid-receptor-dependentLTP in themossy-fiberCA3 systemappearsto haveconstraintsregulatinginductionthat aredifferent from thoseregulatingassociativeNMDA-receptor-dependentLTP. Themossyfibersalsoshowcooperativityin thata sufficientnumberof fibershaveto beactivatedinorderto observeLTP (Derrick& Martinez1994b, McNaughtonetal 1978,butseeChattarjiet al 1989).Inductionof LTP in themossyfibersalsois depend-ent on a sufficient number of tetanizingpulses,presumablyto insure thereleaseof opioid peptides(Derrick& Martinez1994a);peptidesin generalareonly releasedaftertrains ofimpulses(Peng& Horn1991). AssociativeLTP ofmossy-fiberresponsescan be observedwith stimulation of the convergentcommissural pathwayonly whentrainsof mossy-fiberpulsesareused(Der-rick & Martinez1994b).Thecommissural-CA3systemexpressesNMDA-re-ceptor-dependentLTP (Derrick& Martinez1994b),and theinductionof asso-ciative mossy-fiber LTP is blockedby both opioid- andNMDA-receptoran-tagonists(Derrick& Martinez1994b).

Researchfindings in the areaof mossy-fiberLTP are controversial.Al -thoughit is generallyagreedthat LTP in this pathwaydependson trains ofpulses andthepresenceof extracellularCa2+, the site ofCa2+ entry,either pre-or postsynaptically, is in dispute (Wil liams & Johnston1989, Zalutsky &Nicoll 1990), as is the necessity of postsynaptic depolarization (Jaffe &Johnston1990).One group of researchersevenrefuses toascribe thelofty titleof LTP to thephenomenon of synapticenhancementin mossy fibersandrefersto LTP in thispathwayasmossy-fiberpotentiationbecauseit is nonassociativeand,accordingto them,rapidlydecremental(Staubli 1992,Staubliet al 1990).


The controversymayarise because thepreparation of thehippocampal in vitroslice may compromise the integrity of the mossy-fibersystem(Dailey et al1994),anddifferent species,particularlyrat and guineapig, which arefavoritesubjects,havedifferentdistributionsof opioidsandopioid receptors(McLeanet al 1987).Futureresearch,particularly in vivo, shouldresolvesomeof thecontroversy.

ELECTROPHYSIOLOGICAL APPROACHESTORELATING LTPTO LEARNING

Studiesaddressingthecontributionof LTP to learninghavebeenapproachedat anelectrophysiological level to answertwo majorquestions:Doeslearninginducechangesin synapticresponsesthataresimilar to LTP?Doestheinduc-tion of LTP alterlearning?

DoesLearningProduce LTP-likeChanges?

We limi t our reviewto thosestudiesthatmeasuredchangesin thepopulationEPSPratherthan thepopulationspike, owingto generalagreementthat excita-tory postsynaptic potentials(EPSPs)changesreflectchangesin synapticfunc-tion, whereaschangesin the population spike amplitude may reflect othermechanisms(Bliss & Lynch 1988).

Changesin population EPSPscan be observedin perforant-pathdentategyrusresponsesduring exploratorybehaviors.Thephenomenon wasinitiallynamedshort-termexploratorymodulation, or STEM (Sharpet al 1985).Thisinitial study demonstratedthat explorationproducedincreasesin perforant-pathsynapticresponsesover the courseof explorationandthat the increasespersistedfor shortperiods oftimeafterexploration.Theinitial and subsequentstudies(Greenetal 1990)revealedthatSTEMwasnotdependentonhandling,novelty, repeatedstimulation, or increasedlocomotion. Like LTP, STEM re-sults in an apparentincreasein the field EPSPand can be blocked by theNMDA-receptorantagonistMK 801 (Ericksonet al 1990).However,unlikeLTP, STEM is relatively short lived: It lasts only 20–40 min (Sharpet al1985).

Evidencesuggesting that STEM wasnot an LTP-like processemergedin1993 with the report of additive effectsof STEM and LTP (Ericksonet al1993)andchangesin STEM that aredistinct from thoseobservedwith LTP(Ericksonet al 1993).A strongcorrelationbetweenthe magnitude of STEMandsimultaneouslyrecorded2–3°C fluctuations in brain temperature(Moseret al 1993a),presumablyresultingfrom physicalactivity thatoccurredduringexploratorybehavior,also was reported.STEM-like changescould also beinducedwith intenseactivity or with passiveheating.More recentstudies(Moser et al 1993b) suggestthat, when temperature-inducedalterationsin


conductionvelocity are controlled,small changesin perforant-pathdentatefield potentialsmayactuallyreflectchangesdueto exploration.However,thiseffect is shortlived. STEM mayrepresentendogenouslyoccurringshort-termpotentiation (STP),the rapidly decayingprocessthat precedesthe generationof stimulation-inducedLTP.

Ex vivo study is a different approachto the problemof detectingelectro-physiological changesin evokedresponsivenessfollowing learning.The re-sponsivenessof in vitro hippocampal slicesremovedfrom animalsexposedtoan enrichedenvironmentwerecomparedwith responsivenessof slicesfromanimalsexposedto a standardlaboratoryenvironment (Green& Greenough1986). Rearing animals in complex environments produces anatomicalchangesin cortexthatarethought tobearesultof learning(Bennettetal 1964,Greenoughet al 1973, Rosenzweiget al 1962). In this study, the slopeofperforant-pathdentateresponseswasassessed.The magnitudeof field EPSPslopeswaslargerin ratsraisedin a complexenvironmentthanin ratshousedin standardlaboratoryconditions, effects that are similar to thoseobservedafterLTP inductionin this pathway(Bliss & Lomo 1973).Electrophysiologi-cal measuresof antidromic(nonsynaptic) volleysandof thepresynaptic-fibervolley (numberof fibersactivated)revealednodifferencesbetweentherearingconditions. Thus the field EPSPslopeselicited by equivalentvolleys weresignificantly larger, whichsuggeststhat the differencesarisefrom anenhance-ment of perforant-pathsynaptictransmission. The increaseddentaterespon-sivenesswasnot observedin animalsthatwereremovedfrom complexhous-ing threeto four weeksprior to testing, which suggeststhe effects weretransient,as isLTP (Barnes 1979).

More recently, one group of researchersrecordedresponsesin anotherhippocampalsystem,the mossy-fiberprojections,asanimalslearneda radialarm maze (Mitsuno et al 1994). Incremental increases were observed inmossy-fiberfield EPSPsover the courseof learning.Changesin evokedre-sponsivenesswere evident three days after learning.Taken together,thesestudiesshow that learning induceschangesin hippocampalresponsivenessthatresemble thoseobservedfollowing LTP induction.

Why should changes in evoked-responseamplitude following a singlelearningepisodebedetectable?Accordingto theview of distributedmemorysystems,changesunderlying learningshouldoccurin a very small fractionofthe available synapses, andthere is no reasonto expectthat suchsparsechangeswould beevidentin synapticactivationevokedby thestimulationofthousandsof afferentfibersactivatedby a stimulatingelectrode.However,thehippocampalmemorysystemcould havea small capacityand utilize mostsynapseswhen storing information. In such a systeman evokedresponsemight reveal the existenceof a storedmemory.However,in order for newinformation to be stored,the information in this low-capacitysystemwould


eitherhaveto be erasedor haveto decayrapidly. Someresearcherssuggestthatthemossy-fiberprojections to CA3 representa low-capacitystore(Lynch& Granger1986)becauseLTP in mossyfiberscan decay quiterapidly (withinhours) in vitro (Mitsuno et al 1994). However, learning-inducedLTP-likechangesin evokedmossy-fiber responsesare observedthreedaysafter thecessationof training,arguingagainstthe neuralchangesrepresentinga tran-sient,low-capacitystore.

Onecleverstrategyeliminatesthis problemof “looking for a needlein ahaystack.”Synapse-specificchangesin responsesmediatedby a largenumberof afferentsneednot beobserved.Rather,theevokedresponseis employedasan integral part of the learning task. Detectionof salient learning-inducedchangein a large numberof randomly stimulated fibers is not necessary;instead,the activity of the fibers is incorporatedinto the learningtask.Thisstrategywas employedby severallaboratoriesand providesconsistentandconvincingelectrophysiologicalevidence for a role ofLTP in learning.

In one set of studies,a shuttle avoidancetask with a footshock as anunconditioned stimulus was employed(Matthieset al 1986,Ott et al 1982,Reymannet al 1982).High-frequencyperforant-pathstimulationwasthecon-ditionedstimulus.Low-frequencyevokedresponseswere recordedin theden-tate gyrus before,during, and after 10 daily training sessions.Overall dailychangesof the field EPSPsloperoughly correspondedto changesin learnedbehavior.However, the relationships amongthemeasures each day weremorecomplex;improvedperformancewasnot correlatedwith responsemagnitudewithin thedaily trials.TheLTP-like increasein responseswasapparentonly atthe start of the secondday of training, which suggeststhat a consolidationprocessoccursafter the training and prior to the sessionthe following day.Nevertheless,the increasesin the field EPSPparalleledlearningacrossdays,with asymptotic performanceoccurringon the daysof asymptotic LTP. Animportantobservationwas that animalsthat were poor learnersand did notacquirethe task also failed to show an increasein dentateresponses.Thestimulation may haveinducedLTP that was independentof any learning-in-ducedchangesin neuralfunction.However,thestimulationtrainsusedasaCSdid not produceany changes inthe EPSPduring the initial 40 trials on thefirstday of training.Thus,it is notlikely thattheCS stimulation inducedLTP.

An interpretationaldifficulty of theabovestudyis that thehippocampusisnot necessaryfor learningof the active-avoidancetask; in fact, hippocampallesionsor NMDA-receptorantagonists canfacilitateactive-or passive-avoid-ancelearning,respectively(Mondadoriet al 1989,Nadel 1968,Ohki 1982,Shimai & Ohki 1980). Thus increasesobservedin perforant-pathresponsesthatparallellearningmayreflectancillarylearningof otheraspectsof theCS,suchas context (Kim & Fanselow1992). However, in a subsequentstudy,colchicinelesionsof the dentategyrus eliminatedboth the evokedresponse


andthe ability of perforant-pathstimulation to serveasa CS (Ruthrichet al1987).Theselesionsdid not alterconditioning to otherCSsnor did theyalterconditionedemotional responseto thefootshock.Together,thesedatasuggestthat the increasesin responsesof activatedperforant-pathdentatesynapsescontributedto the learningof theCS aspectsof an active-avoidanceresponse.

In a similar study(Larocheet al 1989),high-frequencystimulation servedasa CS for a footshockthat elicited behavioralsuppression.Learningof theperforant-pathstimulation-shockassociationoccurredonly when the trainswereof an intensitysufficient to elicit LTP. Further,inhibition of LTP induc-tion by prior tetanization of commissuralafferents,which inhibits LTP induc-tion by engaging inhibitory mechanisms, produced substantial deficits inlearning.Furthermore,chronicinfusion ofAP5,aselectiveNMDA antagonist,blockedbothLTP inductionand the ability of thestimulationto serve as a CS.A significantcorrelationexistedbetweenthe magnitudeof LTP producedbythesevarioustreatmentsandtheacquisitionof theconditionedresponse.Thedecay of LTP inducedin this behavioralparadigmwasobserved inthe follow-ing 31-dayperiod and correlatedwith retentionof the conditioned response(Laroche et al 1991).

In theexperimentsmentionedabove,it wasassumedthat stimulationof theperforantpathcanserveas a sensory-likeconditioningstimulus. However, thedegreeto which the perforantpath is normally involved in representingasensoryCS is unknown.Further,becausethestimulationproduceda potenti-atedsynapticresponse,thecorrelationbetweenLTP andlearningmayreflectmerelyan increasein the salienceof the perforant-pathstimulation. For thisreasonsuchanapproachmaybeof limi tedutility. An alternativestrategyis tostimulatestructuresor pathwaysthat actuallymediatesensoryinput. Studiesby Romanandcolleagues(Romanetal 1987,1993)usedsuchanapproachbyrecordingmonosynaptic responsesin the olfactory (piriform) cortex elicitedby stimulation of sensoryprojectionsfrom the olfactory bulb (the lateralolfactorytract,or LOT). Thesestudiesarenotablein thattheydepartfrom thestudy of LTP restrictedto the hippocampus and addressthe contribution ofLTP to learning atother cortical sites. Inthese studies,patterned LOTstimula-tion wasusedasa discriminativecuefor thepresenceof water.Stimulation ofthis olfactory pathwayapparentlyproducedsomething like a sensoryevent,becauserats respondedto burst stimulation with sniffing and exploring, asthough they detectedan odor, and such stimulation servedas a CS in anolfactorydiscrimination learningtask.Performancein this taskusingstimula-tion as a CS wasremarkably similar to thatobservedwith actual odorsasCSs.Comparisonof monosynaptic responsesduring the acquisition of discrimina-tion learning revealedincreasesin the monosynaptic LOT piriform cortexresponses,an effect that persistedat least24 hoursafter training. Thus pat-ternedstimulationdid not producesynapticpotentiation unlesstheassociation


of the cue and the water rewardwas learned.A significant correlationwasfoundbetweentheincreasein thefield EPSPslopeandthenumberof correctresponses.Although the magnitudeof LTP andbehavioralresponsesamonganimals was quite variable, better responding was associated with largerchangesin the field EPSPslopeswithin individual animals (Romanet al1993).Of particularinterestis theobservationthattheburststimulation,whichis thought to be optimal for LTP induction at other sites(Staubli & Lynch1987),wasineffectiveby itself in inducing LTP. Rather,a long-termdepres-sion of responseswasobservedfollowing stimulation of naiverats in a non-learningsituation. BecausetheLOT pathwayis known to beresistantto LTPinduction invivo (Racineetal 1983, Stripling etal 1991)butnot in vitro (Junget al 1990,Kanter & Haberly 1993) or during learning(Romanet al 1987,1993),thesedatasuggestthatLTP induction is actively inhibitedin vivo. It istemptingto speculatethatattentionalor othermechanisms areengagedduringconditioning thatenable LTPinductionin this corticalstructure.

Togetherthesestudiesprovidepositive supportfor the ideathat LTP maybe involved in conditioning becauseLTP-like increasesin evokedpotentialsexist following learning in CS pathwaysthat are chosenfor experimentalconvenience.A moredirectexperimentalapproachto thequestionof whetherLTP is a mechanismof learningis to induceLTP andthendeterminewhetherit influences laterlearning.

DoestheInductionof LTP InfluenceLearning?

LTP inducedprior to learningmight impair learningby saturatingLTP proc-essesthat normally participatein the learning; LTP inducedafter learningmight obscureprior learningby occludingany distributedpatternof synapticchangesthat were formed as a result of learning.Alternatively, LTP mayenhanceor impair learningby activatingmodulatorymechanisms (Martinezetal 1991).

In onestudythe effectsof LTP inductionon the acquisition of classicallyconditioned nictitating membraneresponse(NMR) were assessed(Berger1984).Therationalefor this studyarosefrom theobservationthatchangesinhippocampalpyramidal-cellactivity parallelchangesin theacquisition of theconditionedbehavioralresponse(Bergeret al 1983,Berger1984)aswell asfrom thepossibility that the increasein hippocampalunit firing resultedfromplastic eventswithin the hippocampus. LTP inducedunilaterally in the per-forant path facilitatedthe subsequentacquisitionof a classicallyconditionedNMR in rabbits (Berger1984). Given that the hippocampusis not essential forlearningof simultaneousclassicalconditioning of the NMR (althoughit ap-pearsimportantin theacquisitionof morecomplexaspectsof classicalcondi-tioning; seeBerger& Orr 1983), this effect may be of a modulatory nature,rather than a directeffect on an essentiallearningmechanism.


An opposite effect wasobservedusingspatiallearningin a circular maze(McNaughtonet al 1986).Bilateral,supposedlysaturatingLTP stimulation ofthe angularbundle,which carriesboth the lateral and medial aspectsof theperforant-pathprojections,disruptedperformanceeither prior to or immedi-atelyafter learning.In an importantcontrol procedure,LTP thatwasinducedafterthetaskwaswell learneddid notdisruptperformance.Subsequentstudies(Castroet al 1989) expandedthis initial observation.The strategywas tosaturateLTP by stimulating ratseveryday for a 19-dayperiod.On the finalday,theability of theratsto find a hiddenplatformin theMorris watermazewas assessed.A single probetrial was usedto measureperformanceof ratswhen the hidden platform was removed,and the time a rat spent in eachquadrantwas determined.Rats that receivedLTP-inducingstimulation dis-played deficits in learning, whereasrats that receivedonly low-frequencynon-LTP-inducingstimulation acquiredthe task and spentmore time in thequadrantwherethehiddenplatform wasduring acquisition. As a control, theability to locatea visible platformwasassessed,andin this caseno differencewasobservedbetweenthestimulationgroups,which indicatesthat thestimu-lationdid notaffectanysensorycapacity.Ratsin which LTPwas inducedandthenallowedto decaydid notshowanylearningdeficits.Takentogether,thesedatasuggestthat LTP itself, ratherthannonspecificeffectsof stimulation, isessentialfor learning becausesaturation-impaired acquisition of the spatiallearningtask andthe abilityto learnreturned withthe decay ofthe LTP.

Several laboratories,including thelaboratory oforigin, reported difficultiesin replicating the LTP saturationeffect (Jeffery & Morris 1993, Robinson1992,Sutherlandet al 1993).A numberof reasonsmayexplainthe failure toreplicate.First,althoughthestimulation parametersusedmayhaveresultedinthesaturationof LTP in thoseafferentsstimulated,stimulationof theangularbundle with a single stimulation electrodemay not sufficiently tetanizeallfibers that coursethrough this structure.Second,LTP saturationdoesnotprevent the induction of LTD (Linden & Conner 1995), which also is apotentialmemory mechanism(Sejnowski 1977, Stent1973). Otherreasonsforlack of replicationof the LTP saturationeffect were delineatedin a recentstudy(Barneset al 1994)in which LTP saturationinduceddeficits in reversaltraining to a circular maze,but not in a watermaze,which suggestsdifferenttasksusceptibility to LTP saturation. The extentof saturationwasaddressedby measuringthe inductionof the immediateearly genezif, whoseinductionwascorrelatedwith thequantity of LTP induction in thedentate.LTP satura-tion proceduresinducedzif mostly in the dorsal hippocampus.Thus, if zifmarksthosecellsthatpotentiated,thenperhapsLTP wasneithersaturatednorinducedin themoreventralregionsof thehippocampus in thoseexperimentsthat did not replicatethe saturationeffect. Barneset al (1994) believe thisinterpretationis supportedby findingsfrom thesamestudyin which maximal


electroconvulsiveshock(ECS)treatments,which producea synapticpotentia-tion (Stewartet al 1994) that is NMDA-receptor-dependent(Stewart& Reid1994),also led to significantdeficits in acquisition andreversalof the watermazetask.Thepotentiation producedby eitherECSor LTP-inducingstimula-tion was notadditive, andECS induced zif throughoutthe hippocampus.Seizureswereobservedin someanimals, which apparentlydid not influencelearning: When ECS treatmentinducedseizureswithout inducing LTP, nodeficitswereobserved.Thedeficitswerehighly correlatedwith theamountofLTP induced.Although aninterpretationalproblemis thatmultiple ECStreat-mentsmay produceeffectsthat alter learningas a result of actionsthat areunrelatedto the induction of LTP, the results of Barneset al (1994) areconsistentwith the view that a large degreeof hippocampal inactivation isneededto reliably inducelearningdeficits (Jarrard1986,McNaughtonet al1989). Inthis view, informationstored inadistributedmemorysystem isquiteresistantto degradation,andthepartialsaturationof LTP or preservationof aprocess suchas LTD maybe sufficientto permitsubstantial learning.

Although the enhancement of classical conditioning (Berger 1984) andthe impairment of spatial maze learning (Barnes et al 1994, Castro et al1989, McNaughtonetal 1986)apparentlyarecontradictoryeffects,thediffer-encesin thefindings of thesestudiesreflect,in our view, a differentialcontri-butionof thehippocampus,andthereforehippocampalLTP, to classicalcon-ditioning of theNMR and spatiallearning, which aredistinctly differentmem-ory tasksthat appearto requiredistinct memorysystems(Thompson 1992).Becausethehippocampusis not requiredfor acquisition of theNMR responsebut is requiredfor acquisition of spatialmazes,the rolesof LTP in thesetwokindsof learningarelikely different,andthusthestudiescannotbecompareddirectly.

PHARMACOLOGICAL APPROACHESRELATING LTPTOLEARNING

Subsequentto the demonstration of the important role for the NMDA-typeglutamatereceptorsin LTP induction, a numberof behavioralresearchersrushedto characterizetheeffectsof NMDA-receptorantagonistson learning.As in all pharmacologicalstudiesattempting to studylearning,theinferenceofcausalityfrom a specificactionof a drugis problematic(Martinezet al 1991).Drug-relatedside effectsand determinationof the drug’s specificsite ofactionarealwaysissues.Further,in the studiesreviewedbelow, the drug hasto beadministeredbeforetheinitiation of conditioning if it is to block theinductionof anyLTP thatmight contributeto thelearning.Beingthuspresentearly,thedrug might inducean effect on learningthrougha sensory,motor, motiva-


tional, attentional, or other variable(Martinez et al 1991).As notedbelow,these concerns complicate the interpretation of studiesusingthis strategy.

Many studiesexaminedtheeffectof selectiveNMDA-receptorantagonistsonavarietyof learningtasks(Kim etal 1991,Walker& Gold1991),includingtasks thought to depend on hippocampal function (Robinson et al 1990,Staubliet al 1986).Herewe limit our discussionto pharmacologicalstudiesthataddressbothhippocampus-basedlearningandLTP inductionandthatuserelatively localized,or at leastintra-CNS,administration of drugs,so that asfar aspossibletheeffectsdescribedaretheresultof anactionof thedrug in acircumscribedareaof thebrain.Themostcomprehensiveandelegantstudies(Morris et al 1986)examinedintracerebroventricular(ICV) administration ofAP5,theselectiveNMDA antagonist, on learningin aMorris watermazetask.Prior researchindicatedthat thehippocampusis importantin theacquisitionofthis task, that is, when therats arerequiredto learnthelocationof theplatformwith respectto distalcuesin theenvironment(Morris etal 1982). Inthe initialstudies(Morris et al 1986),thenatureof thememoryimpairmentinducedbythe NMDA antagonistwasassessedwith (a) measuresof latencyon acquisi-tion trials, (b) measuresof performanceon a probe trial with the platformremoved,and (c) a reversalprocedure,by which animalswere additionallytrainedwith theplatformin a different location.For eachof thesemeasuresasignificantimpairmentwasobservedin theanimalsinfusedwith AP5. Poten-tial sensorimotor impairmentsinducedby thedrug were assessedwith avisualdiscrimination taskusingthesamewatermazeapparatus.In thiscircumstance,the NMDA antagonist had no apparenteffect. The effect of AP5 on LTPinductionalsowasassessedin thesestudiesto comparethebehavior-impairingandLTP-induction-impairingactionof AP5. LTP wasinducedby stimulationof the perforant-pathdentatesynapse.Thedrug hadno effecton the low-fre-quency evoked responses; however, AP5impaired acquisitionof themaze andAP5 completelyblockedLTP induction.

A striking impairmentof taskacquisition wasnot observed;althoughtheanimalsreceivingAP5showedlongerlatenciesto escapethancontrolanimals,learningin thedrug-treatedgroupparalleledthatin thecontrolanimals. Thusalearningcurve was observed.However,becauseanimalswith hippocampallesionsshowa similar earlyacquisitiondeficit (Morris etal 1982),theauthorssuggestedthat learningin the Morris watermazecaninvolve nonspatial ele-mentsandthatother,hippocampus-independentstrategiesareemployed in theinitial stagesof learning.In this view, spatialdeficitsshouldbemostapparentat thepoint of asymptotic learning,andperformancein theprobetrials shouldbe sensitiveto spatial-learningdeficits.Thus,for manyresearchers,the mostconvincingindication of memorydeficits is observedin the probetrials. Asnotedearlier,in this testthe platform is removed,andthe amountof time ananimal spendsin the quadrantwherethe platform was locatedis measured.


Animals treatedwith the NMDA antagonistshowedno preferencefor theoriginal location of the platform. By contrast,animals that receivedeithersalineor the inactivestereoisomerof AP5 showeda significant preferenceforthe quadrantwhere the platform had beenlocated,which indicatesthat theanimalstreatedwith AP5 hadno spatialmemoryof theplatform.Theacquisi-tion curve, as measuredby decreasedlatencies,thereforeindicatesthat theanimalshad learnedto escape fromthe maze usinga nonspatial strategy.

The resultsof reversaltestsaremoreambiguous(Morris et al 1986).In areversaltest the platform is moved to a location different from that of theoriginal training. The degreeof animals’ learningis reflectedby the persist-enceof the animalsin returningto the placeof original learningandby theacquisition of the new platform location. The animalsthat received AP5showedno acquisition of thenewlocationof theescapeplatform,whereas thecontrol groups showedsubstantialpreferencefor the quadrant of originaltraining andreadily learnedthe new locationof the platform.The interpreta-tional problemwith this studyis thattheAP5-treatedanimals’ performanceatthe beginning of reversaltraining wasaspoor asthe control animals’, whichsuggestsa negativetransfer effect of someoriginal learning.

Othercritics notedthat someratsfell off the platform during training andsuggestedthatthe impairment producedby AP5 was because ofmotor deficits(Keith & Rudy1990).Furthercontrolexperimentssuggestthat falling off theplatformdid not haveanaversiveeffecton performancein watermazelearn-ing (Morris 1990).As an addedmeasure,pretrainingwithin the watermazeusing the visual discrimination taskprior to ICV infusion demonstratedthatthe apparentsensorimotor deficit revealedby platform instability could beovercomeby pretraining.Spatial learning impairments resulting from AP5administration werestill observedin thesepretrainedrats. It hasbeennoted(Keith & Rudy1990)thattheratsreceivingAP5 showedperformancedeficitson thefirst trials beforelearninghadoccurred,andthatthis deficit mayreflecta sideeffectof thedrugon sensorimotor function.However,laterstudiesthatmorecloselyexaminedlearningin theearlytrials showedno effectof moder-atedosesof AP5 on performancein thefirst trial (Daviset al 1992).Goddard(1986)objectedthat thediscrimination learningexperimentis not a goodtestof sensorimotor impairment becauseICV administration of AP5 probablyresultsin lower concentrationsof AP5 atsitesimportant for visualdiscrimina-tion. However,actualmeasurementof the dispersionof AP5 following ICVadministrationshowedthatit wasevenlydistributedwithin thebrain(Butcheretal 1990).Subsequentstudiesindicatedthatlocalizedinfusionof AP5 withinthe visualcortexdid not produceimpairments in the visual discrimination task(Butcheret al 1991). Togethertheseresultssuggestthat the impairmentofperformancein the watermazeproducedby AP5 is the resultof the effectsmediatedby theactionsof thisdrugat hippocampalsites.


As notedby theembattled originators oftheseNMDA-antagonist studies,itwould be erroneousto concludethat AP5 causesthe learningdeficit becauseAP5 blocked LTP (Morris 1989a).AP5 may affect learning, for example,becauseAP5 hasan effect on hippocampalthetarhythm,andtreatmentsthatdisrupt thetarhythm canblock acquisition of learningtasks(Winson 1978).Thus,as discussedabove,many factors impedethe interpretationof a drugeffect,includingtheselectivity of thedrug’s actions,sideeffects,drugdisper-sion,and thesiteof drug action.

Another way to demonstrate that two separatedrug effects,suchas im-pairedspatiallearningandimpairedinductionof LTP, arerelatedis to com-parethe doseresponsecurvesof the drug’s separateeffects.Different doseresponsefunctionsmayshowthat thedrugwasactingon differentprocesses,andidenticaldoseresponsefunctionsmayshowthat thedrugwasactingon acommon process.In subsequent studies (Daviset al 1992) identicaldoseresponsecurveswere observedfor both impairment of spatial learningandblockingof LTP induction. Furthermore,concentrationsof AP5, measuredinthe brain using high-performanceliquid chromatography(HPLC) microdia-lysis, that impairedlearningandthatblockedLTP werethesame;no concen-trationof AP5 wasobservedto block LTP without affectinglearning(Butcheret al 1991).Lastly, theextracellularconcentrationsthatweremeasuredduringthe block of LTP induction in vivo matchedthe concentrationsthat wereeffective in blocking LTP induction in vitro.

Furtherstudies(Morris 1989a)addressedthequestionof theeffectof AP5on both theacquisition andretrievalof a spatial-learning task.The reasoningin thesestudieswasasfollows: NMDA-receptoractivation,although essentialfor LTP induction in manyhippocampalpathways,is not essentialfor eithertheexpressionor themaintenanceof LTP. If AP5 altersmemoryby blockingLTP induction, thenany deleteriouseffectsof AP5 shouldbe limited to theacquisitionperiod,andAP5 shouldnot impair performanceon a spatial-learn-ing taskwhen administered followingtraining.This strategyalsoaddresses, tosome degree, the possible sensorimotor and LTP-independent effects ofNMDA-receptorantagonists,becauseany performancedeficit seenin theseconditions could not be becauseof any effect on acquisition.AP5, wheninfusedinto rats by ICV administration following asymptotic acquisition ofthewatermazetask,hasno effecton the retrievalof learnedspatialinforma-tion, asassessedusingprobetrials.Moreover,in thesesamerats,thedosesofAP5 thathadno effecton performancefollowing trainingeffectivelyblockednewlearningin a subsequentreversaltest.Thelack of effectson performanceof analready learned tasksuggeststhatthe AP5 isnotproducingsensorimotorimpairmentthat interfereswith performanceof thetask.Takentogether,thesestudies provide striking evidence thatAP5mayimpair learningthroughblock-ing the induction of LTP.


Therecentdataimplicatingmetabotropicglutamatereceptorsin theinduc-tion of LTP promptedassessmentof the role of theseglutamatereceptorsinspatial learning.Richter-Levin et al (1994) reportedthat perfusion ofthemetabotropicantagonist[RS]-α-methyl-4-carboxyphenylglycine(MCPG)didnot producedeficits in animalsduring acquisition of a Morris water maze,althougha significantdeficit wasobservedin probetrials given24 h afterthelast training trial. In thesesameanimals, equivalentquantities of MCPGattenuatedthe magnitudebut did not block the induction of perforant-pathdentateLTP. Thusantagonismof metabotropicglutamatereceptorsproducessomedeficitsin LTP andspatiallearning.

Thestudiesemploying NMDA-receptorantagonists to assessthecontribu-tion of hippocampalLTP to learning have beenthe subjectof particularlyintensescrutiny(seeKeith & Rudy1990).However,in our view, thefact thatspatiallearningis not blockedcompletelyby NMDA-receptorantagonists isnot surprising. Severalpathwaysin thehippocampus, includingthemossy-fi-ber pathway(Derrick et al 1992), the lateral perforantpath to areaCA3(Breindl et al 1994),andthe lateralperforantpathto dentate(Bramhamet al1991a,b;but see Zhang& Levy 1992) display LTPµ and LTPδ, which are bothopioid receptor-dependentand NMDAreceptor-independent.In addition,bothNMDA-receptor-dependentandNMDA-receptor-independentmechanisms ofLTP inductionareobservedwithin the CA1 region(Teyler & Grover1993).As mentioned above wi th respect to the saturation experiments ofMcNaughtonandcolleagues,whenviewedfrom theperspectiveof distributedmemories,partial sparingof function may be sufficient to permit learning.Suchreasoningleadsto the conclusionthat the alterationof any one of theLTP systemswithin thehippocampusmaynot besufficient to producea totalor evena profounddeficit in spatiallearning.That localizedNMDA-receptorblockadedoesproduceobservabledeficits,andthat thesedeficits aresimilarto, althoughless severethan, those observedwith extensivehippocampallesions,suggestnot only that NMDA-receptor-dependentmechanisms,andperhapsLTP, contribute to spatiallearning,but alsothattheymaybea funda-mentalmechanismof informationstorage.

DoesLearningof a Spatial Task InvolveHippocampalOpioidSystems?

Given that opioid receptor antagonistsimpair the induction of LTP inopioidergicafferents,opioid receptorantagonistswould beexpectedto impairspatiallearning.However,systemicadministrationof naloxoneis reportedtofacilitateacquisitionof aspatialwatermazeas measuredby latency to findtheplatform(Deckeret al 1989).Thesestudiesemployedintraperitonealadmini-stration of naloxone 5min prior to training,which maybe insufficient timefor


intraperitoneallyadministerednaloxoneto block sufficiently opioid receptorsat centralsites.For example,intraperitonealnaloxoneeffectson evolvedhip-pocampalresponsesare observedonly 10–15min following intraperitonealnaloxoneadministration (Martinez & Derrick 1994).Thus training may nothavebeengiven at an optimum time following drug administration. In addi-tion, opioid antagonistsexerteffectson opioid systemsthatinfluencelearningthat may beindependent of hippocampalopioid systems(Martinezetal 1991),andalterationsin theseopioid systemsby systemicadministrationof opioidreceptorantagonistsmay alsoalter learning.In supportof this interpretation,other studiesemploying local applicationof opioids into the hippocampusproducean impairmentof spatiallearning.For example,local administrationof dynorphinsimpairs spatiallearning(McDanielet al 1990),anddynorphinsimpair LTP inductionin boththemossy-fiberCA3 andperforant-pathdentatesynapsesvia actionson kappareceptors(Wagneret al 1993,Weisskopf et al1993).To date,no studieshaveaddressedthe effect of selectiveblockadeofhippocampalµ or δ receptorsin spatiallearning,but local blockadeof opioidreceptorsis likely to producespatial learning deficits because,like opioidreceptorblockade(Derrick et al 1992),elimination of specificmetabotropicglutamatereceptorsselectivelyimpairsmossyfiber LTP, andeliminationofthesemetabotropic receptorsalso impairs spatial learning (Conquet et al1994).

KNOCKOUT MUTANTS, LTP, AND HIPPOCAMPALLYDEPENDENT LEARNING

Themolecularbiological revolution hasarrivedin forcein theareaof LTP andlearning. A paradoxof learning is that it is expressed asactivity amongneurons, thoughthe biological changesthat underlie memories arestoredwithin neurons.The molecular biological revolution taughtus that enduringalterationsof cell function, as must occur in long-termmemorystorage,arecontrolled by gene expressionand resultantprotein production.Thus, forevery sustainedmemory there is likely a chain of eventsleading from theinitiation of activity at a synapticreceptor,to theactivity of secondmessengersystems, tointermediate earlygeneinduction, andto secondarygeneinductionin everycell thatparticipatesin thememorynetwork.Thesameis likely truefor LTP (butsee Lisman1989).

A numberof researchgroupsareendeavoringto tracethechainof cellulareventsthatunderlieinduction andmaintenanceof LTP (Grantetal 1992,Silvaet al 1992a,b).In thesestudiessinglegenes,controlling whatarehopedto bespecificeventswithin cells,canbe eliminatedandthe resultanteffect canbestudiedsimultaneously inwholeanimalsminusonegene,so-calledknockouts,for LTP andlearning.In this methodthegeneof interest,usuallya well-char-


acterized gene, iscloned andin mostcasesalteredso that importantregulatoryregionsof the geneare nonfunctional. This alteredDNA is introduced intoembryonicstemcells derivedfrom blastocysts.The genecombineswith theDNA of the stem cells, and those cells in which the gene is insertedatappropriateregionsof the DNA (via homologousrecombination) canbe iso-latedandinsertedinto developingblastocysts. Subsequentcells arisingfromthesealteredcells all lack the knockoutgene.The resultinganimal is a het-erozygouschimera(combination of normalandmutantcells) that,with crossbreeding, cangenerate progeny that arehomozygous forthe knocked-outtargeted gene.

Onereasonto targetgenesis that thesegeneticprocedureshavethepoten-tial to overcomethe currentlimi tationsof pharmacology. In studiesof genesrelatedto LTP, an areaof focus in the studyof transgeneshasbeenkinases.Although datastronglysuggestLTP induction involvesa variety of kinases,includingproteinkinaseC (Malinow et al 1989),calmodulinkinase(Malenkaet al 1989),andtyrosinekinases(O’Dell et al 1991),thesestudiesarelimitedby the fact that currently availablekinaseinhibitors lack a high degreeofselectivity.Further,for agivenkinase,the kinasefamily to which it belongsiscomposedof a numberof subtypes,which appearto havevariedfunctions. Itwould be of greatutili ty to selectivelyimpair the function of specifickinaseisoforms,a feat thatis achieved bythe use ofknockoutmutants.

The first studythatattemptedto tracetheeventsunderlyinginduction andmaintenanceof LTP (Grantet al 1992)comparedvariousknockoutsof genescodingfor particulartyrosinekinases.Deletionof onespecifictyrosine kinasefound inthefyngene alteredthe amountof current necessary to induceLTP inareaCA1. Traditionalmeasuresof synapticfunctionappeared normal,suchasthe maximal EPSPamplitudesand measuresof paired-pulsefacilitation, ashort-termaugmentation of synapticresponsethatappearsto dependon resid-ualpresynapticCa2+. Thefyn-knockout ratsappearedincapableof learningthelocationof a hiddenplatformin a Morriswater maze.

Unfortunately, this study is difficult to interpret.First, the hippocampusdisplayedobviousanatomicalabnormalities,including an increasein granuleand pyramidal cells. The dendritesof pyramidal cells in stratumradiatumshoweddisorganization andwerelesstightly packed,aswerethecell bodies.Given the alteredneuralarchitecture,the synapticvolume might havebeenreduced,whichmayexplainthereducedability of high-intensitystimulationtoproduceLTP, althoughthis is perhaps unlikely because low-frequency evokedEPSPamplitudesin thefynknockoutsarenotdifferentfrom thoseof wild-typecontrols.Therewere impairments in visual function becausefyn knockoutswere initially poor at performinga visual discrimination wherethe platformwas visible, althoughthey eventuallyreachedlatenciescomparableto wild-typecontrols.Theauthorsalsonotedthat “overtrainingin spatialtasksmasked


the fyn learningdeficit.” Apparently then, the animalscould learn, and thedeletionof the fyn geneonly alteredthesensitivity of theknockoutanimalstosuchparametricaspectsof training asthe numberof training trials neededtoevidencelearning.BecausethefynknockoutscouldexpressLTP, thesedatadonot supporta conclusionthatLTP is a substrateof memory,becauseLTP andlearning clearlydo not depend onthe presenceof thefyngene(Deutsch 1993).

In asecondwaveof studies otherresearchers(Silvaetal 1992b)engineeredknockoutmice thatweredeficientin α-calcium-calmodulin-dependentkinaseII (α-CaMKII). Thekinaseα-CaMKII, in contrastwith tyrosinekinaseFYN,is locali zed to the brain and is neuron specif ic. The α-CaMKII mutantsshowednoovertphysicalor neuroanatomicalabnormalities.Measuresof post-synapticfunction, such as the maximal EPSPamplitudes, in Schaffer-CA1responsesappearednormal,but paired-pulsepotentiation wasreducedin mu-tantmice.Activation of NMDA receptorsappearedto elicit normalresponses.Although theprobability of induction of LTP was greatly reducedin themutants,LTP in someanimalswasvirtually indistinguishablefrom LTP ob-served inwild-typecontrols.

A subsequentstudy (Silva 1992a)assessedthe ability of α-CaMKII mu-tantsto learntheMorris watermaze.Thesemutants apparentlyhada defectintheir visual function, becausethey showedan initial deficit in the visualdiscrimination task. However, thesemutantmice eventually matched the wild-type animalsin performance.The α-CaMKII mutants werealso impairedintheir ability to find the hiddenplatform on the first sessionof training in theMorris watermazeandwerealwaysslower thanthe wild-type control mice;that the mutantsdid learnis shownby the fact that their latenciesto find theplatform decreasedover sessions.For the probetrial, the mutantmice tookroughly twice as long to find the platform. An additional test employedarandomlylocatedplatform.Sometrials wereconductedwith thehiddenplat-form randomlylocatedat othersites.Mutantmice took aslong to find refugeat therandom sitesasto find refuge at theoriginal location,whereaswild-typemice took lesstime to find the original locationandlonger timesto find therandomplatforms,which indicatesnegativetransfer.Theresultsof therandomprobe test thereforesuggestthat the mutant mice did not know the spatiallocation of the hiddenplatform, althoughthey apparentlywere able to usesomestrategyto escapethe maze.Mutant animalswere the equal of theirwild-type cousinsin learning a + maze,which doesnot exact any spatialability from its students. The α-CaMKII mutantsshowedgreateractivity inopen field and did not evidencehabituation of activity. Thus the evidencesuggeststhat the α-CaMKII mutants did havea deficit in the ability to learnthespatialmaze.Whatis not soclearis whether this spatialdeficit isrelatedtoLTP. In the mutantmice only the probability of LTP inductionwasaltered;LTP induction wasnot abolished.If amutant didshowLTP, thentheLTP was


indistinguishable from that observedin wild-type controls. The deficit inpaired-pulsepotentiation in the mutant mice is also problematic. Such analterationcould be important for hippocampal function that is unrelatedtoLTP butthatis manifestedasa spatialdeficit.

Another group targetedprotein kinaseC (Abeliovich et al 1993) and se-lectedthePKCγ isoform,bothbecauseinhibitors of PKC preventinduction ofNMDA-receptor-dependentLTP in CA1 (Malinow et al 1989) and becausePKCγ is specific to neuronsin the CNS and is expressedpostnatally. Theprobabilityof LTP induction wasreducedin themutantsmuchasit hadbeenin previousstudies employingknockouts;but if the mutantmice were firsttreatedwith low-frequencystimulation, then the LTP was indistinguishablefrom that observed in wild-type controls.An interesting finding, however,wasthatexpressionof LTD wasnot impaired.In spiteof coordination deficits,themutantmice learnedthe Morris watermazeat the samerateasdid the wild-type controlsand performedsimilarly in the probeand randomprobetests.Theauthorsbelievethemutantmicedid exhibit a mild spatialdeficit becauseduring the probetest the mutantscrossedthe hiddenplatform site lessoftenthan the controls,eventhoughthey were searchingthe correctquadrant.Incontrastwith their behaviorin the spatialmaze,the PKCγ mutantsdid showdeficits in contextual-fear conditioning in that they froze significantly lessafterreturnto a chamberwheretheyexperiencedfootshock.Thereis evidencethatacquisitionof acontextual-feartaskdependsonboththehippocampusandNMDA receptors (Kim etal 1991, 1992; Kim &Fanselow1992).Conditionedfear(measuredby observingfreezingin responseto a tonein a novelenviron-ment),which is thoughtto be independentof hippocampal function,wasnotimpaired.The resultsdo not supporta role for PKCγ in eitherLTP or spatiallearningbecausethe mutantmice could learn the Morris watermazeand, ifstimulated appropriately,displayedLTP.

Departingfrom the studyof the kinases,othergroupstargetedgenesspe-cific for subtypesof theglutamatereceptor.Onegroup(Sakimuraet al 1995)createdmice with a mutation of the GluRε subunit of the NMDA-receptorchannel.No obviousmorphologicalbrainabnormalitieswereobserved,prob-ably becausethis geneis expressedafterdevelopment. However,themutantsappearedjumpy andhadan apparentlyenhancedstartleresponse.LTP couldbe inducedin the mutantsbut at a reducedmagnitude (smaller percentageincreasefrom baseline).As in the caseof the PKCγ mutants,low-frequencystimulation prior to LTP restoredsomefunction but not to the level of thewild-type control. During training in the Morris water mazethe mutantsshowedan initial latency deficit that disappearedby the end of training.During the transfertestthemutants searchedthepreviouslycorrectquadrant,crossedthe trainedsite—though not at the samelevel of efficiency as thewild-type mice—andwereless precise intheir crossings.Theauthors consider


their findings positive evidencefor the participation of the GluRε subunit oftheNMDA receptorin bothLTP andtheacquisitionof spatiallearning.Yet,asin theotherstudiesreviewed,thegenemutation did not abolisheitherLTP orspatiallearning,in which case thisgene cannotbe necessary for either.

The metabotropicglutamatereceptor(mGlu) is implicatedin LTP induc-tion, thoughthis conclusion remains controversial(Bashir etal 1993, Manzoniet al 1994). Activation of the metabotropicglutamate receptor1 (mGluR1)may activateG-protein-coupled secondmessengerprocesses,andtheseproc-essesmay play an important role in LTP induction, acting like a metabolicswitchthatenablestheinductionof LTP. Recentlyoneresearchgroupcreatedan mGluR1mutantto testinvolvementof mGluR1 in LTP andcontextual-fearconditioning (Aibaet al1993). Thisreceptorsubtype is plentifulin thedentategyrusandCA3 areasandis apparentlyrestrictedto thepresynapticsideof theSchaffercollateralprojectionto areaCA1. ThesemGluR1 mutants hadataxiaandwerepoor breedersbut hadbrainsthat appearednormal.Synaptictrans-mission, STP,andpaired-pulsepotentiation werenormal.LTP wasobservedin the mGluR1 mutants, but asin the GluRε mutants its magnitudewasreduced.Low-frequencypriming had no effect. The mGluR1 mutantswereimpairedin thehippocampus-dependentcontextual-fearconditioning taskandexhibitedlessfreezingthandid thewild-type controlsin thecagewheretheywereshocked.By contrast,the mutants learnedaswell asthe wild-type ani-mals to freezein responseto the tone and thus showednormal learninginresponse to this hippocampus-independent form of fearconditioning. Theauthorsconcludedthat themGluR1receptoris not necessaryfor induction ofLTP butthatit modulates neural plasticity, apparently expressed asthe magni-tudeof LTP. Becausethe mutantanimalsweremoderatelyimpaired in theirlearning,Aiba et al positedthat the mGluR1 receptoris not necessaryforlearningof the contextual-fearresponse butperhaps participatesin someway.

A quitedifferentsetof resultswasfoundby anothergroupwho createdanmGluR1mutant(Conquetet al 1994).Thesemutants exhibitedataxiaaswell.A neurological examof the mutantsrevealeda completelossof the rightingreflex andreducedlocomotoractivity. LTD in cerebellarsliceswasseverelyreduced.Synaptic transmission appearednormal in the Schaffercollateral-commissural pathwayto CA1, medialandlateralperforantpathwaysto den-tate,andmossy-fiberandassociationalpathwaysin CA3. LTP wasnormalinall pathwaysexceptthe mossy-fiberCA3 pathway,whereit was greatly re-duced.In the visible platform versionof the Morris water mazethe mutantmice were initially slower than the wild-type mice, but after threesessionsthey were indistinguishablefrom controls.However,in the hidden-platformversionof the maze,the mGluR1 mutantscould not find the platform andevidencedno learning.Becausethemutantmicedid learnthevisually guidedmaze, the authorsconcludedthat the deficit observedwith respectto the


hidden platform was due to an impairment of spatial ability mediatedbymGluR1receptorsandprobablyin themossy-fiberCA3 system,becauseLTPwasreducedonly in the mossy fiber-CA3system. If theauthors’ interpretationof the datais correct,thendeficits in themossy-fiber systemcannotbe com-pensatedby correctlyfunctioningNMDA-receptor-dependentsystemsin otherhippocampalpathways.This suggestsan importantrole for both the dentategyrusandLTPµ in its mossy-fiberprojectionsto areaCA3 in learning(Marr1971,McNaughtonet al1989).

TheknockoutstrategyhasprovidedsomeevidencethatLTP andLTD aresubstratesof learning.Whattheknockoutgainsin specificityof elimination islessenedby the complexity of the mutant creaturethat developswithout aparticulargene.For example,is synaptictransmission in the mutantnormal?In both the knockoutstudiesandstudiesusingselectivedrugs,it is assumedthat if low-frequencysynaptictransmissionis not altered,thensynaptictrans-missionis normal.However,thereis no reasonto believethat normalhippo-campalfunction involvesexclusivelylow-frequencyactivity; rather,high-fre-quencyinformation is important for aspectsof hippocampalfunction inde-pendentof its potential involvementin LTP induction. Suchactivity may begreatlyinfluencedby theabsenceof a gene,asevidencedby thealterationsinfacilitation in one study (Silva et al 1992b).Other basicquestionsconcernwhetheran animal’s motor systemis competentto performwhat is requiredandwhetherthe animalcanseethe elevatedplatform. We find it curiousinthesemutantstudiesthat learningis measuredin vivo andinduction of LTP ismeasuredin vitro in the hippocampal slice. This strategyis basedon theas-yet-uncertainassumption thatLTP observedin theslice is identicalto thatobserved invivo.

The most striking study, the last in this review, is undoubtedlythat byConquet et al(1994), in which fivepathways inthehippocampuswerecharac-terizedfor normalsynaptictransmission andinductionof LTP. The learningdeficit, which was impressive,may be relatedin an unexpectedmannertomalfunctioning in the mossy-fiber system, a pathway known to exhibit NMDA-receptor-independent, opioid-receptor-dependent LTPµ (Derrick et al 1991, Har-ris & Cotman1986).Prior to this study,mostresearchers assumedNMDA-re-ceptor-independentLTP had a relatively unimportant role and attachedpri-mary importanceto NMDA-receptor-dependentLTP in spatiallearning.

To befair, however,theknockoutstudiesdo demonstratedeficitsin hippo-campal LTPthat mirror deficits in hippocampus-dependent learning, andif weapply the sameexplanationof gracefuldegradationas we havepreviously,then it is not surprisingthat somememoryis evidentin a distributedneuralsystem.

However,it remainsdisquieting that, evenwithin a discreteafferentsys-tem,nosinglespecifickinaseappearsessentialfor theinductionof NMDA-re-


ceptor-dependentLTP. Suchfindings,suggesting asthey do the existenceofparallel intracellularcascades,areproblematicfor reductionists trying to de-lineatethe essentialcomponents of a successivemolecularcascade.From alargerview, theseresultsemphasizethatno singleapproachwill besufficientto elucidatetheroleof LTP in memory,eventhoughtheknockoutapproachispowerfulandincreasesourunderstandingof therelationshipbetweenLTP andlearning.

CONCLUSION

The rationalefor consideringLTP a memorymechanismis strong.The ab-sence of proof that LTP is involved in memoryresults from our currentuncertaintiesaboutwhatmemoryis andhow we shouldobserveit. Theoccur-renceof multiple formsof LTP, togetherwith thedistributednatureof hippo-campalinformation storage,makesit difficult to identify theprocessesneces-sary to hippocampalmemory and to implicate specific LTP processes inmemory.Thuswe shouldproceedcautiouslyin interpretingnegativefindings.Might LTP emergeasanepiphenomenonunrelatedto learningor memory?Ifit does,thenthe focusof researchwould shift to suchotherpotentialneuralmechanismsof memorystorageas LTD, populationspike potentiation, andpresynapticfacilitation.After 20 yearsunderscrutiny,however,LTP remainsthe bestsinglecandidatefor the primary cellular processof synapticchangethatunderlieslearning andmemoryin the vertebrate brain.

ACKNOWLEDGMENTS

The writing of this review wassupportedby DA 04195,NSF 3389,andtheEwing Halsell Endowmentof The University of Texasat SanAntonio. Wethank ProfessorsDavid Jaffe,Ray Kesner,Mark Rosenzweig,Tracy Shors,and RichardThompsonfor their helpfulcomments.

Any Annual Reviewchapter, aswell asany arti clecited in an Annual Reviewchapter,may bepurchased fromthe Annual ReviewsPreprints and Reprints service.

1-800-347-8007; 415-259-5017; email: [email protected]

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