Synapses and Memory Storage

Synapses and Memory Storage

Mark Mayford1, Steven A. Siegelbaum2, and Eric R. Kandel2

1The Scripps Research Institute, Department of Cell Biology, La Jolla, California 920372Columbia University, Kavli Institute for Brain Science, Howard Hughes Medical Institute,Department of Neuroscience, New York, New York 10032

Correspondence: [email protected]

The synapse is the functional unit of the brain. During the last several decades we haveacquired a great deal of information on its structure, molecular components, and physio-logical function. It is clear that synapses are morphologically and molecularly diverse andthat this diversity is recruited to different functions. One of the most intriguing findings is thatthe size of the synaptic response in not invariant, but can be altered by a variety of homo-and heterosynaptic factors such as past patterns of use or modulatory neurotransmitters.Perhaps the most difficult challenge in neuroscience is to design experiments that revealhow these basic building blocks of the brain are put together and how they are regulated tomediate the information flow through neural circuits that is necessary to produce complexbehaviors and store memories. In this review we will focus on studies that attempt to uncoverthe role of synaptic plasticity in the regulation of whole-animal behavior by learningand memory.

The idea that learning results from changesin the strength of the synapse was first sug-

gested by Santiago Ramon y Cajal (1894) basedon insights from his anatomical studies. Thatmodulation of synaptic connectivity is a criticalmechanism of learning was incorporated intomore refined models by Hebb in the 1940s and1950s. The experimental investigation of theseintriguing conjectures required the develop-ment of behavioral systems in which one couldexamine changes in the neuronal componentsof a specific behavior during or after the mod-ification of that behavior with learning (Kandeland Spencer 1968).

SYNAPTIC CHANGES WITH LEARNING

Procedural Memory in Simple Systems

The first attempts to identify neuronal changesthat underlie learning and memory used simpleforms of procedural memory such as habitua-tion, sensitization, and classical conditioning.From 1969 to 1979 several useful model sys-tems emerged: the flexion reflex of cats (Spenceret al. 1966); the eye-blink response of rabbits(Thompson et al. 1983); and a variety of reflexbehaviors in invertebrate systems, includingthe gill-withdrawal reflex of Aplysia (Kandeland Tauc 1963), the escape reflex of Tritonia

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(Willows and Hoyle 1969), and various behav-ioral modifications in Hermissenda (Alkon1974), Pleurobranchaea (Mpitsos and Davis1973), Limax (Gelperin 1975), crayfish (Krasne1969), and honeybees (Menzel and Erber 1978).These preparations were chosen for the limitednumber of neurons (or neuronal types) thatparticipated in the behavior. This reductionistapproach allowed the specific circuitry that con-trolled the behavior to be defined and examinedfor modification following learning. The studieswere aimed at pinpointing the sites within aneural circuit that are modified by learningand used for memory storage, and for identify-ing the cellular basis for those changes.

By allowing electrophysiological recordingfrom individual neurons that are readily identi-fiable from animal to animal and that form partof a simple behavioral circuit, these systems pro-vided the first experimental insight into the cel-lular mechanisms of memory. One mechanismfor learning and short-term memory, evident inboth the gill-withdrawal reflex of Aplysia and inthe tail-flick response of crayfish, is a change insynaptic strength brought about by modulatingthe release of transmitter. A decrease in trans-mitter release is associated with short-term ha-bituation, whereas an increase in transmitterrelease occurs during short-term dishabituationand sensitization (Castellucci et al. 1970, 1974,

1976; Zucker et al. 1971; for early reviews, seeKandel 1976; Carew and Sahley 1986). The plas-ticity occurred at the sensory neuron inputsonto the motor neurons that control the reflexresponse and thus directly modulate its magni-tude. These studies provided the first evidencefor the idea that behavioral memory is mediatedby plasticity in the synaptic connections be-tween neurons that participate in the behavior.

Cell biological studies of the connectionsbetween the sensory and motor neurons ofthe gill-withdrawal reflex in Aplysia revealed abiochemical mechanism for the short-term in-crease in transmitter release produced by sensi-tization (Fig. 1) (Kandel 2001). A single noxious(sensitizing) stimulus to the tail leads to theactivation of three known classes of modulatoryneurons. The most important releases seroto-nin, which acts to increase the level of cAMPin the sensory neurons. This in turn activatesthe cAMP-dependent protein kinase (PKA),which enhances synaptic transmission. Inject-ing cAMP or the catalytic subunit of PKA di-rectly into the sensory neurons is sufficient toenhance learning-related transmitter release(Brunelli et al. 1976; Castellucci et al. 1976).

Studies of the gill-withdrawal reflex also re-vealed that even elementary forms of learninghave distinct short- and long-term stages ofmemory storage. Whereas one training trial

Before learning Short-term sensitization Long-term sensitization

Gene activatorCREB-1



AC AC AC

G G

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Tail TailSerotonin Serotonin

Ca+ channel Ca+ channel Ca+ channel

G PKA PKA PKAGrowth

Sensoryneuron

Motor neuron

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Enhanced glutamaterelease

Enhanced glutamaterelease

CRE CRE CRE

Figure 1. Short-term and long-term sensitization of the gill-withdrawal refex in Aplysia involves posttransla-tional modifications and alterations in protein synthesis. (Left) The gill-withdrawal circuit. A tactile stimulus tothe siphon causes a sensory neuron to release glutamate to excite a motor neuron. (Center) A shock to the tailcauses serotonin release from interneurons. This activates a stimulatory G protein (G), which activates adenylylcyclase (AC), leading to production of cAMP and PKA-dependent phosphorylation of different substrates,including Kþ and Ca2þ channels, which enhances glutamate release from the sensory neuron terminals. (Right)Repeated shocks to the tail elicit a persistent increase in cAMP, leading to altered gene transcription and proteinsynthesis. This leads to growth of new synapses.

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gives rise to a short-term memory lasting min-utes, repeated spaced training gives rise to long-term memory lasting days to weeks (Carew et al.1972; Pinsker et al. 1973). These behavioralstages have a parallel in the stages of the under-lying synaptic plasticity—a short-term formlasting minutes to hours and a long-termform lasting days to weeks (Carew et al. 1972;Castellucci et al. 1978). In addition to the im-mediate and short-term changes in synapticfunction with learning, profound structuralchanges accompany the storage of long-termmemory in both habituation and sensitizationof the gill-withdrawal reflex. The sensory neu-rons from habituated animals retract some oftheir presynaptic terminals so that they makefewer connections with motor neurons and in-terneurons than do sensory neurons from con-trol animals (Bailey and Chen 1983, 1988a). Incontrast, following long-term sensitization thenumber of presynaptic terminals of the sensoryneurons increases more than twofold (Baileyand Chen 1983, 1988a). This learning-inducedsynaptic growth is not limited to sensory neu-rons. The dendrites of the postsynaptic motorneurons also grow and remodel to accommo-date the additional sensory input (Bailey andChen 1988b). These results show that clearstructural changes in both the pre- and postsyn-aptic cells can accompany even elementaryforms of learning and memory in Aplysia andserve to increase or decrease the total number offunctional synaptic connections critically in-volved in the behavioral modification.

Together, these early cellular studies of sim-ple behaviors provided direct evidence support-ing Ramon y Cajal’s suggestion that synapticconnections between neurons are not immuta-ble but can be modified by learning, and thatthose anatomical modifications serve as ele-mentary components of memory storage (Bai-ley and Kandel 1993). In the gill-withdrawalreflex, changes in synaptic strength occurrednot only in the connections between sensoryneurons and their motor cells but also in theconnections between the sensory neurons andthe interneurons (Hawkins et al. 1981; Frost andKandel 1995). Thus, memory storage, even forelementary procedural memories, is distributed

among multiple sites. The studies showed fur-ther that a single synaptic connection is capableof being modified in opposite ways by differentforms of learning, and for different periods oftime ranging from minutes to weeks for differ-ent stages of memory.

Studies of memory in invertebrates also de-lineated a family of psychological concepts (Haw-kins and Kandel 1984) paralleling those firstdescribed in vertebrates by the classical behav-iorists (Pavlov and Thorndike) and their mod-ern counterparts (Kamin, Rescorla, and Wag-ner). These concepts include the distinctionbetween various forms of associative and non-associative learning and the insight that contin-gency—that the conditioned stimulus (CS), inassociative learning, is predictive of the uncon-ditional stimulus (US)—is more critical forlearning than mere contiguity; this is the CSthat must precede the US by a short interval oftime (see, for example, Rescorla and Wagner1972). Such psychological concepts, whichhad been inferred from purely behavioral stud-ies, could be explained in terms of their under-lying cellular and molecular mechanisms. Forexample, the finding that the same sensory-to-motor neuron synapses that mediate the gill-withdrawal reflex are the cellular substrates oflearning and memory illustrates that proceduralmemory storage does not depend on special-ized, superimposed memory neurons whoseonly function is to store rather than processinformation. Rather, the capability for simpleprocedural memory storage is built into theneural architecture of the reflex pathway (Cas-tellucci and Kandel 1976).

Declarative Memory and the Hippocampus

In the mammalian brain two major early threadsof research were critical in moving the study ofmemory forward to the point that the questionof cellular and synaptic mechanisms couldbegin to be addressed. The first thread was an-atomical and revealed a remarkable localiza-tion of memory function in the mammalianbrain. Studies of patients with damage to the me-dial temporal lobes revealed that there are twomajor memory systems in the brain: declarative


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(explicit) and procedural (implicit or nonde-clarative). Declarative memory, a memory forfacts and events—for people, places, and ob-jects—requires the medial temporal lobe andin particular the hippocampus (Scoville andMilner 1957; Squire 1992; Schacter and Tulving1994). In contrast, procedural memory, a mem-ory for perceptual and motor skills also evidentin invertebrate animals, involves a number ofbrain systems depending on the specific typeof learning and in the most elementary in-stances uses simple reflex pathways themselves,as discussed above for simple systems. Althoughthese seminal studies identified important clas-sifications of memory and helped to solidifythe notion of functional localization at a broadanatomical level, they did not provide insightinto the mechanisms acting at the finer levelof the individual neuron or synapse. This nextstep forward was made in rodent studies, inwhich the hippocampus plays a similar role indeclarative types of memory, such as memoryfor place.

In 1971 recordings of single unit firing inthe hippocampus of awake, freely moving ratsrevealed that neurons in the hippocampus reg-ister information not about a single sensorymodality—sight, sound, touch, or pain—butabout the space surrounding the animal, a featthat depends on information from severalsenses (O’Keefe and Dostrovsky 1971). Thesecells, referred to as “place cells,” fire selectivelywhen an animal enters a particular area of thespatial environment. Based on these findings,O’Keefe and Nadel (1978) suggested that thehippocampus contains a cognitive map of theexternal environment that the animal uses tonavigate. These studies helped to define therole of the hippocampus in declarative memoryas a multimodal integrator and mapmaker. Al-though spatial location is a strong componentof this hippocampal map, the human lesionstudies and work from Howard Eichenbaumin rodents suggest that it may be a more generalintegrator of memory-specific associations(Squire and Stark 2004)

Nearly contemporaneous with the discov-ery of place cells, the synaptic responses in thehippocampus were found to display plasticity

with several features advantageous for memorystorage (Bliss and Lømo 1973). Stimulationwith a high-frequency train of action potentialswas shown to produce a prolonged strengthen-ing of synaptic transmission in all three of themajor hippocampal pathways. This long-termpotentiation (LTP), which is discussed in detailin the article by Luscher and Malenka (2012) inthis collection, has several forms that differ inmolecular mechanism and duration (Fig. 2).In both the perforant path synapses from ento-rhinal cortex to dentate gyrus and Schaffer col-lateral synapses from CA3 to CA1 pyramidalneurons, LTP follows learning rules first postu-lated by Hebb. It requires that presynaptic ac-tivity be closely followed by postsynaptic activ-ity. In the mossy fiber pathway, LTP does notfollow Hebb’s rules; it requires only presynapticactivity with no coincident postsynaptic activity(Bliss and Collingridge 1993).

The Hebbian form of LTP has been the focusof intense interest as it became clear that it pos-sessed many other features useful for a synapticmechanism for certain forms of learning. Thesecritical features of LTP are synapse specificity,cooperativity, and associativity. LTP is synapsespecific in that it is only induced at synapsesthat are activated by the tetanic stimulation;neighboring synapses that are not active donot undergo potentiation. LTP is cooperativebecause multiple inputs must be activated si-multaneously to produce sufficient postsynap-tic depolarization to induce LTP. Finally, LTP isassociative because when a weak input that isnormally insufficient to induce LTP is pairedwith a strong input, the weak input will nowbecome potentiated. These features can largelybe explained by the behavior of the N-methyl-D-aspartate (NMDA)-type glutamate receptor,whose activation is critical for the inductionof the Hebbian form of LTP (see Luscher andMalenka 2012). Unlike most neurotransmitterreceptors that respond simply to the presence orabsence of their cognate transmitter in the syn-aptic cleft, the NMDA receptor is also sensitiveto the state of the postsynaptic membrane inwhich it resides. Under normal resting condi-tions a Mg2þ ion present in the NMDA recep-tor pore blocks ion flux. However, this Mg2þ

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blockade can be relieved by depolarization ofthe postsynaptic membrane, which expels theblocking ion through electrostatic repulsion.Thus, NMDA receptors are only active whenthere is both glutamate present because of pre-synaptic activity and the postsynaptic neuron issubstantially depolarized. LTP is therefore pro-duced only at synapses from a given presynapticneuron that are active (leading to glutamate re-lease) and impinge on a postsynaptic neuronthat receives sufficient concurrently active in-puts (associativity and cooperativity) to pro-duce enough depolarization to relieve Mg2þ

blockade of the NMDA receptor. As a result,LTP conforms to the type of learning ruleHebb suggested: “When an axon of cell A isnear enough to excite cell B and repeatedly orpersistently takes part in firing it, some growthprocess or metabolic change takes place in oneor both cells such that A’s efficiency, as one ofthe cells firing B, is increased.”

Activation of NMDA receptors produces aninflux of postsynaptic Ca2þ that is critical to the

induction of LTP (Lynch et al. 1983; Malenkaet al. 1988). In addition to LTP, which is rou-tinely induced at hippocampal synapses by briefhigh-frequency (100-Hz) stimuli, hippocampalsynapses also show a form of long-lasting syn-aptic depression, or LTD, with prolonged low-frequency stimulation. Surprisingly, this formof plasticity also requires activation of NMDAreceptors and postsynaptic Ca2þ. The directionof the synaptic change likely depends on themagnitude and dynamics of the postsynapticCa2þ signal, as well as on the current state ofthe synapse, for example, whether it has beenrecently potentiated.

LTP and LTD were identified and have beenstudied primarily using artificial electrical stim-ulation that activates large numbers of fibers ina manner that is unlikely to occur naturally.The discovery of a spike-time-dependent formof synaptic plasticity (STDP) (Markram et al.1997; Magee and Johnston 1997) was an impor-tant advance in providing a physiologicallyplausible manipulation that induced synaptic

LTP

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One train Four trains

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Protein synth.

Protein synth.

100 Hz

1 Hz

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5 Hz

VGCCser/thr kinase tyr kinase

mGluRp38 MAPK

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Figure 2. Multiple forms of long-term synaptic plasticity may contribute to learning and memory. (Top) A singletrain of high-frequency tetanic synaptic stimulation can produce forms of long-term potentiation (LTP) ofsynaptic transmission lasting 1–2 h. This early LTP (E-LTP) does not require changes in transcription ortranslation. Different patterns of tetanic stimulation can recruit distinct forms of E-LTP that differ in molecularmechanism and site of expression. Multiple trains of tetanic synaptic stimulation can induce a more persistentform of synaptic plasticity that can persist for many hours. This late LTP (L-LTP) requires altered gene expres-sion, activation of PKA, and new protein synthesis. (Bottom) Weaker forms of synaptic activity can lead to along-term depression of synaptic transmission (LTD). Different patterns of synaptic stimulation recruit distinctforms of LTD through differing signaling pathways.





plasticity. In STDP a synapse becomes potenti-ated if a postsynaptic spike follows presynapticrelease, whereas the synapse becomes depressedif the postsynaptic spike precedes release. Theplasticity occurs within a tight time windowsuch that release and spike activity offset bymore than 40 ms produce no synaptic change.STDP is also NMDA receptor dependent andis likely to incorporate some of the molecularmechanisms of LTP and LTD studied using lessphysiological stimuli, although there are clearlysome important differences, as we shall see below.

Although the properties of NMDA-depen-dent synaptic plasticity are intriguing and pro-vide a straightforward cellular mechanism forforming learned associations, it has been signif-icantly more difficult to provide direct experi-mental links between LTP and behavior. In 1986pharmacological studies made the first connec-tion of LTP to spatial memory by showing thatNMDA receptors must be activated to form thistype of memory in the rat. When NMDA recep-tors are blocked pharmacologically, not only isLTP blocked, but the animal can no longer formspatial memories that are dependent on the hip-pocampus. This was shown using the Morriswater maze, in which an animal must integratemultiple visual cues to form a spatial memory ofthe location of a platform submerged below thesurface of a water bath (Morris et al. 1986).Importantly, blockade of the NMDA receptorsdoes not impair the ability of an animal to learnto swim to the platform when it is visible, a taskthat does not require the hippocampus.

Similarly, the pharmacological blockade ofNMDA receptors has been found to alter thestability of the place fields of hippocampal placecells (Kentros et al. 1998). When animals areplaced in the same environment two days in arow, they activate substantially the same ensem-ble of hippocampal place cells whose place fieldsare similar in position and size on each day. Thisis consistent with the idea that these cells encodea stable map of the environment. However, if anNMDA blocker is administered during the for-mation of this place map, then the place-cell-firing pattern is not stable over 24 h.

These results provide a causal link betweenNMDA receptor function, long-term place cell

stability, and long-term spatial memory. It istempting to think that these effects are linkedby a causal requirement for LTP or LTD in theseprocesses; however, a number of caveats shouldbe kept in mind. For example, certain geneticmanipulations that disrupt hippocampal LTPdo not impair forms of memory believed torequire the hippocampus (e.g., Zamanillo et al.1999). Conversely, manipulations that do notalter hippocampal LTP can disrupt spatiallearning (Shimshek et al. 2006).

One of the most difficult problems in link-ing synaptic plasticity mechanisms to behaviorin declarative memory is the sparse and distrib-uted nature of the circuits. How the variousneural representations of the environment aremodified with learning, the location of the crit-ical sites of plasticity, and how these modifiedcircuits are recruited to alter motor behavior ina memory test are still largely unclear. Thismakes interpreting the effects of a single typeof pharmacological manipulation quite diffi-cult. One approach that has been taken inboth simple and complex models is to applymolecular and genetic approaches to provide aricher understanding of the underlying mecha-nisms of plasticity and to use the tools generatedto probe the links to behavior.

Procedural Fear Memory in the MammalianAmygdala

Some of the strongest evidence linking learningand memory to LTP comes from experimentsfocused on the amygdala, which is essential forboth instinctive and learned fear (Davis et al.1994; LeDoux 1995, 1996). When an animal isgiven a shock to the foot paired with a tone—aclassical conditioning paradigm—the animalexhibits a learned fear response by freezing inresponse to the tone alone. This form of learn-ing is known to involve the amygdala, a regionof the brain that receives direct auditory infor-mation from the thalamus and processed infor-mation from neocortex, and which provides anoutput to the hypothalamus that regulates au-tonomic fear responses. Neurons in isolatedslices of amygdala undergo LTP in response totetanic stimulation protocols similar to those

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used in the hippocampus. Importantly, behav-ioral pairing of a tone and shock, which in-duces fear learning, also potentiates synaptic re-sponses in the amygdala to auditory stimuli invivo (Rogan et al. 1997). Following fear learningthe synaptic response to electrical stimulationof auditory inputs in isolated amygdala slices isalso enhanced (McKernan and Shinnick-Gal-lagher 1997). Moreover, this synaptic enhance-ment must be closely related to LTP becausebehavioral fear conditioning occludes the abilityto induce LTP in isolated amygdala slices inresponse to high-frequency stimulation (Tvset-kov et al. 2002).

SYNAPTIC AND MOLECULAR MECHANISMSOF PLASTICITY AND LEARNING

Procedural Memory in Invertebrates

Molecular biology revealed a remarkable con-servation of mechanism underlying short-termmemory among different animals. In 1974 Sey-mour Benzer and his students discovered thatDrosophila can learn fear and that mutations insingle genes interfere with short-term memory.Flies with such mutations do not respond toclassical conditioning of fear or to sensitization,suggesting that the two types of learning havesome genes in common (Quinn et al. 1974; Du-dai et al. 1976). Identification of the causal mu-tations in the fly revealed that they representedone or another component of the cAMP path-way, the same pathway underlying sensitizationand classical conditioning in Aplysia (Byerset al. 1981). These early studies that pointed tothe central role of cAMP signaling examinedshort-term memory lasting only a few minutes.The next step was to ask how the short-termchanges become stabilized to last days or years.

The first clue to how short-term memory isswitched to long-term memory came whenLouis Flexner observed that the formation oflong-term memory requires the synthesis ofnew proteins (Flexner et al. 1963). Subsequentwork in Aplysia (Dash et al. 1990; Bacskai et al.1993; Martin et al. 1997; Alberini et al. 1994;Hegde et al. 1997; for review, see Kandel 2001)and Drosophila (Dudai et al. 1976; Duerr and

Quinn 1982; Drain et al. 1991; for review, seeWaddell and Quinn 2001) showed that withrepeated training PKA moves from the synapseto the nucleus of the cell, where it activates thetranscription factor cAMP response elementbinding protein-1 (CREB-1). CREB-1 acts ondownstream genes to activate the synthesis ofprotein and stimulate the growth of new synap-tic connections.

Further studies in Aplysia and in the fly re-vealed the surprising finding that the switch tolong-term synaptic change and the growthof new synaptic connections is constrained bymemory suppressor genes (see Abel et al. 1998).One important constraint on the growth ofnew synaptic connections is CREB-2 (Yin et al.1994; Bartsch et al. 1995), which when over-expressed blocks long-term synaptic facilita-tion in Aplysia. When CREB-2 is removed, asingle exposure to serotonin, which normallyproduces an increase in synaptic strength lastingonly minutes, will increase synaptic strength fordays and induce the growth of new synapticconnections.

Declarative Memory

Molecular and pharmacological studies in hip-pocampal slice preparations have identifiedsome of the key signaling events that are trig-gered by Ca2þ influx through the NMDA recep-tors during the induction of LTP (Fig. 3). Theinitial Ca2þ signal activates directly or indirectlyat least three critical protein kinases in the post-synaptic neuron: (1) calcium calmodulin-de-pendent kinase II (CaMKII) (Malenka et al.1989; Malinow et al. 1989); (2) protein kinaseC (PKC) (Routenberg 1986; Malinow et al.1988); and (3) the tyrosine kinase Fyn (O’Dellet al. 1991; Grant et al. 1992). These findingsprovided a catalog of targets for manipulationusing advances in mouse genetics that allowedfor the selective deletion or knockout of indi-vidual genes in the whole animal. The generalstrategy was to delete a gene critical for LTP andto then examine both synaptic plasticity andbehavioral learning and memory in the sameanimal to test the idea that LTP is a key molec-ular event important for memory storage.





The first set of studies applied these tech-niques to examine the importance of the a sub-unit of CaMKII and the tyrosine kinaseFyn. Genetically altered mice lacking either ofthese kinases were viable and survived to adult-hood. However, in each line of mutant micehippocampal LTP and spatial memory were im-paired. These results extended the link betweenhippocampal synaptic plasticity and memory,first established pharmacologically with NMDAreceptor blockers, and outlined a genetic ap-proach for exploring the mechanisms of synap-tic and behavioral plasticity. Genetics is the goldstandard for determining molecular function inmodern biology, and its application to complexquestions of neurophysiology and behavior inthe mammalian brain opened up a myriad ofmolecular questions that were previously inac-cessible. However, it soon became clear that theapproach suffered a number of drawbacks forthe study of circuits and behavior that have

stimulated several important technical refine-ments.

A major question regarding the molecularmechanism of LTP is whether it is expressedpresynaptically, involving an increase in gluta-mate release; postsynaptically, depending on anincrease in the postsynaptic response to gluta-mate; or through a coordinated change in pre-synaptic and postsynaptic properties. A numberof apparently contradictory results have beenreported in the literature over the past 30 years.However, in our view much of the controversyresults from the fact that neurons can expressmultiple forms of LTP that may differ in theirsynaptic locus, molecular mechanisms, time-scale, and role in learning and memory (Fig. 2).

The controversy dates back to some of theearliest studies of LTP. Measurements of radio-labeled glutamate binding to hippocampalmembranes indicated that LTP was postsynap-tic, caused by an increase in the number of

Presynaptic

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CaMKll

Retrogradesignal

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GluR1

PKC

GluR1

SOMA

To synapse

Effector GenesCREB-1

Long-term Short-term

MAPK

cAMP

AC VGCC

CAMKIV

PKA

Figure 3. Molecular mechanisms for induction of LTP and memory. These basic signaling pathways have beenimplicated in both NMDAR-dependent LTP and behavioral learning. Short-term plasticity (lasting severalhours) is produced by NMDAR-dependent Ca2þ signaling to protein kinases and the recruitment of newglutamate receptors to the synapse. Long-term plasticity (lasting days) requires CREB-dependent gene activa-tion in the nucleus by the action of multiple protein kinases. Long-term plasticity and memory also requiressynthesis of a constitutively active isoform of PKC.

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postsynaptic glutamate receptors (Lynch et al.1982). At the same time another study conclud-ed that LTP was presynaptic, based on the find-ing of increased levels of extracellular glutamatefollowing induction of LTP (Dolphin et al.1982). The interpretation of such early studieswas complicated by the fact that they did notdirectly assess synaptic function. Rather, it wasthe finding that LTP in the Schaffer collateralpathway is associated with a selective increasein the AMPA-type receptor component of theexcitatory postsynaptic potential with littlechange in the NMDA-type receptor componentthat provided the first evidence that LTP at thissynapse is both initiated and expressed postsyn-aptically (Kauer et al. 1988). Later it was foundthat the increase in response of the AMPA re-ceptors to glutamate during LTP is attributableto the rapid insertion of new clusters of recep-tors in the postsynaptic membrane from a poolof intracellular receptors stored in recycling en-dosomes (Carroll et al. 1999; Shi et al. 1999; Parket al. 2004; Nicoll et al. 2006). Other studies,however, have implicated additional presynap-tic changes following induction of Schaffer col-lateral LTP (Bolshakov and Siegelbaum 1994;Zakharenko et al. 2001; Emptage et al. 2003;Enoki et al. 2009). As nearly all studies ofSchaffer collateral LTP indicate that its induc-tion requires Ca2þ influx into the postsynapticcell, the finding that LTP may involve an increasein transmitter release implicates the need forone or more retrograde messengers that are re-leased from the postsynaptic cell to enhance re-lease from the presynaptic cell. As discussed be-low, whether LTP is presynaptic or postsynaptic(or both) likely depends on the frequency orpattern of stimulation used to induce plasticity.

Changes in presynaptic function associatedwith LTP can be assayed selectively by measur-ing the rate of release of a fluorescent dye, FM 1-43, from synaptic vesicles in the presynaptic ter-minals when the vesicles release their contentsby exocytosis in response to presynaptic stimu-lation (Ryan et al. 1996). When LTP is inducedusing a 50-Hz tetanic stimulation, there is nochange in the rate of dye release in response topresynaptic action potentials, suggesting thatthe expression of 50-Hz LTP is purely postsyn-

aptic. However, when LTP is induced usingstronger 200-Hz or theta burst stimulation pro-tocols, there is a marked increase in the rate ofdye release, suggesting an enhanced presynapticfunction (Zakharenko et al. 2001) that appearsto develop more slowly than the enhancementin AMPA receptor response (Bayazitov et al.2007). The presynaptic and postsynaptic formsof LTP also show a differential dependence onNMDA receptors. Whereas 50-Hz LTP is fullyblocked by the NMDA receptor antagonist APV,200-Hz and theta burst LTP recruit an NMDAreceptor–independent form of LTP that re-quires activation of L-type voltage-gated Ca2þ

channels (Grover and Teyler 1990; Zahkarenkoet al. 2001). Genetic evidence for the existenceof distinct presynaptic and postsynaptic loci ofLTP has been provided by studies of AMPA re-ceptor– and brain-derived neurotrophic factor(BDNF)-knockout mice.

The GluR1 (GluRA) AMPA receptor sub-unit is important for the activity-dependentpostsynaptic insertion of AMPA receptors withLTP. Knockout mice carrying a deletion in GluR1show a severe deficit in “standard” NMDA-de-pendent LTP induced by high-frequency stimu-lation, as might be expected from previous stud-ies. Surprisingly, these mice were not impairedin long-term spatial memory as seen with pre-vious knockouts or NMDA receptor antagoniststhat blocked LTP (Zamanillo et al. 1999). Sub-sequent studies showed that not all forms of LTPwere impaired in these mice; for example, a com-ponent of theta burst LTP was spared (Hoffmanet al. 2002). Moreover, not all spatial learningwas intact; a short-term form of spatial workingmemory was impaired in the knockout animals(Reisel et al. 2002).

A line of mice in which the BDNF gene wasselectively deleted in the forebrain shows rela-tively normal LTP in response to a 50-Hz tetan-ic stimulus (Zakharenko et al. 2003). However,these mice have a significant reduction in LTP inresponse to 200-Hz or theta burst tetanic stim-ulation. Moreover, the ability of these strongLTP protocols to produce a presynaptic en-hancement in the rate of FM 1-43 release iscompletely blocked in the mutant mice. Thesedata support the view for separable components





of presynaptic and postsynaptic LTP that can bedifferentially recruited by distinct patterns ofphysiological activity. Interestingly, whereas areduction in NMDA receptor–dependent LTPis observed as animals age, and is correlated withan age-related decline in memory, older animalsshow an increase in L-type Ca2þ channel–de-pendent LTP (Shankar et al. 1998). Moreover,L-type Ca2þ channel antagonists improve mem-ory in older animals (Deyo et al. 1989).

Clearly the relationship between LTP andmemory is more complex than a simple 1:1 cor-respondence. Different forms of LTP have dif-ferent underlying molecular mechanisms anddifferent roles in behavior that we are just be-ginning to unravel (e.g., Woodside et al. 2004).

Long-Term Memory

Procedural and declarative memories differ dra-matically. They use a different logic (unconsciousvs. conscious recall) and they are stored in differ-ent areas of the brain. Nevertheless, these twodisparate memory processes share several molec-ular steps and an overall molecular logic. Both arecreated in at least two stages: one that does notrequire the synthesis of new proteins and one thatdoes. In both, short-term memory involves co-valent modification of preexisting proteins andchanges in the strength of preexisting synapticconnections, whereas long-term memory re-quires the synthesis of new proteins and thegrowth of new connections. Moreover, bothforms of memory use PKA, mitogen-activatedprotein kinase (MAPK), CREB-1, and CREB-2signaling pathways to convert short-term to long-term memory. Finally, both forms appear to usemorphological changes at synapses to stabilizelong-term memory (Bailey et al. 2008).

Long-term potentiation in the hippocam-pus proved to have both early and late phases,much as long-term synaptic facilitation in Aply-sia does. One train of stimuli produces the earlyphase (E-LTP), which lasts 1–3 h and does notrequire protein synthesis. Four or more trainsinduce the late phase (L-LTP), which lasts atleast 24 h, requires protein synthesis, and is ac-tivated by PKA (Frey et al. 1993; Abel et al.1997). The role of this L-LTP has been investi-

gated genetically using mice that express a mu-tant gene that blocks the catalytic subunit ofPKA, or that carry an inhibitory mutation inthe CREB-1 gene. Both lines of mice have aserious defect in long-term spatial memoryand both have roughly similar defects in LTP.The early phase is normal but the late phase isblocked, providing evidence linking the phasesof LTP to the phases of memory storage (Silvaet al. 1992a,b; Bourtchouladze et al. 1994; Huanget al. 1995; Abel et al. 1997). Finally, an inter-mediate phase of LTP that requires PKA but notnew protein synthesis can be induced by twotrains of stimuli (Winder et al. 1998). Theoret-ical studies indicate that these multiple com-ponents of plasticity are necessary to generatelong-lasting memories in the face of ongoingsynaptic plasticity (Fusi et al. 2005).

Procedural Memory in Vertebrates

We now have a good understanding of the neu-ral circuit and molecular mechanisms underly-ing learned fear and of the role of synaptic plas-ticity in fear memory, thanks to the work ofJoseph LeDoux, Michael Davis, Michael Fanse-low, and James McGaugh. Pairing of a tone witha foot shock leads to a conditioned fear responseto the tone alone, which elicits freezing behaviorin the conditioned animal. This conditionedfear response depends on the long-term poten-tiation of the auditory response in neurons ofthe amygdala (Johansen et al. 2011). Both thesynaptic changes and the persistence of thememory for learned fear require PKA, MAPKs,and the activation of CREB (Won and Silva2008). Moreover, similar to mechanisms ofNMDA receptor–dependent LTP, learned fearrequires the enhanced trafficking of AMPA re-ceptors to the synapses of amygdala neurons(Rumpel et al. 2005). In contrast to learnedfear, when a tone predicts a period of safetywhen an animal is protected from the footshock, there is a long-term depression of theauditory inputs to the amygdala (Rogan et al.2005). Thus, learned fear and learned safety in-volve opposing changes in synaptic strength.

Eye-blink conditioning is produced by pair-ing a tone (the CS) with an aversive air puff to

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the eye (the US), resulting in a learned eye blinkthat is appropriately timed to the paired US(Thompson et al. 1983). Theoretical and exper-imental studies have proposed that the condi-tioning involves a relatively simple cerebellarcircuit. Prior to learning, activation of cerebellarPurkinje neurons in response to the CS leads toan inhibition of neurons in the interpositus nu-cleus (one of the deep nuclei of the cerebellum),thereby inhibiting motor output. With condi-tioning there is a decrease in the Purkinje cellactivity in response to the CS, resulting in dis-inhibition of the neurons of the interpositusnucleus, leading to eye blink. This model is con-sistent with findings that Purkinje cell activitycan be reduced as a result of LTD at the excit-atory parallel fiber synaptic input onto the Pur-kinje neurons (Ito 2001). This decrease in thestrength of the parallel fibers occurs when theclimbing fiber inputs to the cerebellum are ac-tivated in appropriate temporal proximity toparallel fiber activity. Thus, the Purkinje cellsbecome less responsive to input, as a result ofa down-regulation of AMPA receptors at theparallel fiber to Purkinje cell synapse.

The similarity between the changes in syn-aptic function and both procedural and declar-ative learning in the mammalian and inverte-brate central nervous systems supports the viewthat alterations in synaptic strength represent anevolutionarily conserved general mechanism ofmemory formation. Moreover, studies of fearlearning, eye-blink conditioning, and modifica-tions of the vestibular–ocular reflex (Lisbergeret al. 1987; Boyden et al. 2006), as well as habit-uation in Aplysia and crayfish, provide supportfor the role of both synaptic potentiation andsynaptic depression as parallel mechanisms formemory storage.

Synapse-Specific Local Protein Synthesisand Learning Networks

There is now significant evidence from variousforms of learning in a number of different spe-cies that the critical changes that store informa-tion in the brain occur at specific synapses with-in a circuit. The finding that long-term memoryand synaptic plasticity involve changes in gene

expression and therefore the nucleus of thecell—which is shared by all the synapses of theneuron—raises the question of how the geneproducts required for long-term memory influ-ence the specific synapses that were altered toproduce the immediate and short-term memo-ry. Studies in both Aplysia (Martin et al. 1997)and the hippocampus (Frey and Morris 1997)suggest that the synaptic modifications associ-ated with short-term plasticity leave a molecularmark or “tag” on the synapses that were modi-fied. The presence of the synaptic tag allowsthose synapses to specifically capture and usenewly synthesized gene products arriving fromthe nucleus to stabilize the initial changes pro-duced with learning.

How is a synapse marked? Two distinctcomponents of marking have been identifiedin Aplysia, one that requires PKA and initiateslong-term synaptic plasticity and growth, andone that stabilizes long-term functional andstructural changes at the synapse and requires(in addition to protein synthesis in the cellbody) local protein synthesis at the synapse(Martin et al. 1997). Because mRNAs aremade in the cell body, the need for the localtranslation of some mRNAs suggests that thesemRNAs may be dormant before they reach theactivated synapse. If that were true, one way ofactivating protein synthesis at the synapse wouldbe to recruit a regulator of translation at theactivated synapse that is capable of activatingdormant mRNA. In Xenopus oocytes, maternalRNA is silent until activated by the cytoplas-mic polyadenylation element binding protein(CPEB) (Richter 1999). In Aplysia a new iso-form of CPEB (ApCPEB) with novel propertieswas found in neurons. Blocking this isoform ata marked (active) synapse prevented the main-tenance but not the initiation of long-term syn-aptic facilitation (Si et al. 2003a,b). Indeed,blocking ApCPEB blocks memory days after itis formed. An interesting feature of this isoformof Aplysia CPEB is that its amino terminus re-sembles the prion domain of yeast prion pro-teins and endows it with similar self-sustainingproperties. But unlike other prions, which arepathogenic, ApCPEB appears to be a functionalprion. The active self-perpetuating form of the





protein does not kill cells but rather has the im-portant physiological function of maintaininglong-term synaptic facilitation.

THE EMERGENCE OF A SYSTEMSAPPROACH TO MEMORY STORAGE

The application of molecular and genetic toolsand the use of simple systems have allowed us totest some of the foundational theories of Cajaland Hebb regarding the cellular mechanisms oflearning. There are a number of commonalitiesthat have been established across multiple spe-cies, such as:

1. Synaptic change is elicited by patterns ofneuronal activity at critical points within abehavioral circuit.

2. Both increases and decreases in synapticstrength can contribute to behavioral plas-ticity.

3. Synaptic plasticity has similar temporal andmolecular properties to behavioral learning,e.g., short- and long-term phases dependenton discrete signaling pathways.

4. Apparently different forms of learning usesimilar underlying cellular and molecularmechanisms.

One of the remaining challenges in rigorous-ly testing some ideas in the mammalian nervoussystem is the problem of sparse encoding in dis-tributed networks and the identification of theengram, the physical or functional memory tracepresent in a neural network posited by Lashley(1950). Although the fine-tuning of the hippo-campal representation of the world and the sen-sitization of the gill-withdrawal reflex in Aplysiamay recruit some of the same underlying molec-ular mechanisms, the changes in the hippocam-pus are dispersed throughout a large structurewith no clear anatomical segregation. And al-though the hippocampus plays a critical role inmemory, the formation of complex associationsmust involve activity in multiple brain areas.How can the dispersed circuits for a givenspecific memory or complex representation be

isolated and functionally probed in the samemanner as a reflex circuit in a simple system?

Several advances in the optical and molec-ular toolbox for circuit analysis in mammals arelaying the foundation to answer this type ofquestion. Advances in in vivo optical imagingtechniques have enabled the visualization ofplastic changes in neuronal properties associat-ed with learning and memory (Hubener andBonhoeffer 2010). Such changes can involve al-terations in morphology of preexisting syn-apses, including the enlargement of dendriticspines (the sites of a pyramidal neuron’s excit-atory input) during LTP and spine shrinkageduring LTD (Kasai et al. 2010). Additionalstructural changes may involve the growth ofnew synaptic connections, implied by the ap-pearance of new dendritic spines following in-duction of synaptic plasticity. That such struc-tural changes may contribute to learning andmemory is supported by a recent study thatreported the growth of new dendritic spines inmotor cortex neurons following motor learning(Xu et al. 2009).

One area of rapid progress is in the intro-duction of genetically encoded molecules thatallow the selective activation or suppression ofthe neurons in which they are expressed withlight (Zhang et al. 2007a,b; Zhao et al. 2008;Airan et al. 2009). A great advantage of light-regulated channelrhodopsin or halorhodopsinis that they allow precise millisecond temporalcontrol over action potential firing such that agenetically tagged group of neurons can be firedin a controlled pattern simply by patterning thelight pulses. Also effective for turning neuronson or off are ligand-gated proteins with custom-ized binding sites, such as the G-protein-cou-pled designer receptor (Alexander et al. 2009)and a chimeric ligand-gated ion channel, whichare activated by an inert ligand (Magnus et al.2011). These systems are allowing sparse butgenetically defined neural cell types (e.g., inhib-itory neurons) to be manipulated selectivelywithin a background of many other functionallydistinct cell types.

What defines a circuit in the mammalianbrain? At one level there is a clear, developmen-tally controlled pattern of connectivity, for

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example, the hippocampal trisynaptic circuit ora cortical column. Although this canonical con-nectivity is clearly an important constraint onfunction, what is remarkable is that these cir-cuits can represent so many different externalevents or encode a wide range of memories.Clearly, any individual neuron can participatein many different representations or memories,and at a deeper level a neural circuit is definedby what it represents. That is, we could define acircuit as all the neurons that are recruited dur-ing the recognition of an individual’s home, orduring the recollection of one’s last holiday.How many neurons does it take to form a spe-cific memory? How predetermined are thesecircuits? How are they modified during learningand differentially recruited during recall? Andhow can a new memory be formed throughaltered synaptic strength without overwriting apreexisting memory encoded in a neuron’s syn-apses? Some new genetic techniques are begin-ning to probe these questions.

Competition between neurons is necessaryfor refining neural circuitry, but does it play arole in encoding memories in the adult brain? Instudies of fear conditioning it was found thatthe introduction of excess or constitutively ac-tive CREB into a sparse subset of amygdala neu-rons caused those neurons to be specifically re-cruited to encode the memory to which theanimals were subsequently trained (Han et al.2007). Conversely, if such neurons are deletedafter learning, that specific fear memory isblocked while other fear associations stay intact(Han et al. 2009). This study reveals that there isgreat flexibility in the particular group of neu-rons recruited to any given memory, at least inthe amygdala, and that the resting state of theneuron governs the probability that it will berecruited.

Long-term memory requires transcription-al activity, and genes such as cfos, zif268, and arcare rapidly and transiently induced by high-fre-quency neural activity and have been used formany years to map brain activity patterns inrodents. By providing a genetic readout of pat-terns of neural activity, these genes provide thepotential to obtain direct molecular controlover ensembles of neurons based on their re-

sponse to a given experience. In one study thecfos promoter was combined with elements ofthe TETregulatory system in transgenic mice toallow the introduction of a lacZ marker intoneurons activated with fear conditioning (Re-ijmers et al. 2007). The marker provided a long-lasting record of brain activity during learningthat could be compared to activity during recall.A partial reactivation of the neurons active dur-ing learning occurred, and the strength of therecalled memory was correlated with the degreeof circuit reactivation. More importantly, thisapproach provides an opportunity to introduceany genetically encoded effector molecule intoneurons based on their recent activity, provid-ing the potential to study circuits based on thespecific memory they encode.

Why are there so many forms of synapticplasticity that differ in their mechanism of in-duction, time of persistence, and synaptic locus(Fig. 2)? An interesting insight into this ques-tion was provided by a theoretical study thatapproached the question of how a memorycan persist in the face of the barrage of synapticinputs and synaptic plasticity that a neuron ex-periences during an individual’s lifetime. Al-though it was impossible to encode robustmemories with a single form of plasticity, mul-tiple forms of plasticity with distinct timescalesof induction and persistence were able to yieldpersistent memory storage (Fusi et al. 2005). Achallenge in the future will be to examine howthe diverse array of plasticity mechanisms mayindeed cooperate and interact to yield a unifiedmechanism of long-lasting yet ongoing memo-ry storage.

SUMMARY

We now understand in considerable moleculardetail the mechanisms underlying long-termsynaptic plasticity and the importance thatsuch plastic changes play in memory storage,across a broad range of species and formsof memory. One surprising finding is the re-markable degree of conservation of memorymechanisms in different brain regions withina species and across species widely separatedby evolution. However, although it is now clear





that long-term synaptic plasticity is a key step inmemory storage, it is important to note that asimple enhancement in the efficacy of a synapseis not sufficient to store a complex memory.Rather, changes in synaptic function must occurwithin the context of an ensemble of neurons toproduce a specific alteration in informationflow through a neural circuit. With the recentdevelopment of powerful genetic tools, it maysoon be possible to meet the daunting challengeof visualizing and manipulating such changes inneural circuitry. A second important challengeis to understand how the basic processes ofmemory storage are altered with age or disease,including Alzheimer’s disease. There is nowcompelling evidence that defects in memorystorage result from pathological changes in thefundamental mechanisms underlying long-term synaptic plasticity. Thus, it becomes ofcritical importance to understand in sufficientdetail both the basic mechanisms of memorystorage and the changes that take place in dis-ease to design specific compounds that can beused to restore cognitive function.

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