Triggers and substrates of hippocampal synaptic plasticity

Neurosctence & BIobeha~loral Revwws. Vol 15. pp 415--423 v Pergamon Press plc. 1991 Printed m the U S A 0149-7634/91 3 00 + 00

Triggers and Substrates of Hippocampal Synaptic Plasticity

G U Y M A S S I C O T T E * A N D M I C H E L B A U D R Y t I

*Department of Chemistry and Biology, University of Quebec at Trois-Rivieres, CP 500, Trois-Rivieres, Quebec, Canada G9A-5H7

"PProgram in Neural, Informational and Behavioral Sciences, University of Southern California, HEDCO Neurosciences Building, Los Angeles, CA 90089-2520

Rece ived 15 June 1990

MASSICOTTE, G AND M BAUDRY Triggers and substrates of htppocampal svnapnc plastwtty NEUROSCI BIOBEHAV REV 15(3) 415-423, 1991.--It Is widely assumed that behavioral learmng reflects adaptive properties of the neuronal networks underlying behavior Adaptive properties of networks m turn arise from the existence of biochemical mechamsms that regulate the efficacy of synapnc transmission. Considerable progress has been made in the elucldat~on of the mechamsms revolved m synaptlc plastlc,ty at central synapses and especially those responsible for the phenomenon of long-term potentmtton (LTP) of synapt~c transmission tn hlppocampus Whale the nature and the timing requirements of the mggenng steps are reasonably well "known, there ~s stdl a lot of uncertainty concerning the mechamsms responsible for the long-term changes. Several b~ochermcal processes have been proposed to play critical roles m promoting long-lasting modifications of synapttc efficacy Th~s review examines first the triggers that are necessary to produce LTP in the hippocampus and then the different b~ochemlcal processes that have been considered to partlopate in the maintenance of LTP Finally, we examine the relationships between LTP and behavioral learning

Hlppocampus Plasticity Long-term potentmt~on

IN both the peripheral and the central nervous system (CNS), synaptic transmission exhibits various forms of plastlcity and many theorists assume that learning and memory processes are manifestations of long-lasting mo&fications of synapt~c transmission. Remarkable progress In our understanding of the mechanisms underlying adaptive changes m synaptlc operation has been accomplished m recent years Studies of learning m simple nervous systems have produced some of the most exciting and important results in the neurobiological analysis of memory (2, 43, 44). In particular, they have provided convincing evidence that certain biochemical features readily explain short-term modifications of synaptlc transmission As these features (e.g., second messengers and enzymatic cascades integrating several regulatory signals) are shared with higher vertebrate species, it is generally assumed that similar mechanisms can account for some properties of learning and memory from Aplysla to hu- mans. However, this approach has so far provided only tentative explanations of how synaptic efficiency could be altered in a quasi permanent way. Furthermore, questions about the bio- chemistry of memory have been further comphcated by the recent recognition that the brain possesses multiple memory systems (108) and there is evidence that different forms of memory might be underlaid by different molecular mechanisms (20). Thus, generalizations of the mechanisms underlying synaptlc plasticity from simple systems to "higher brain" structures ( e .g , cortex) in mammals are not necessarily obvious.

In mammalian brain, synaptic efficacy can be altered promptly and lastingly by appropriate patterns of electrical stimulation.

~Requests for repnnts should be addressed to Michel Baudry

The most striking example of synaptlc plasticity is long-term potentiation (LTP) that occurs primarily m the hippocampus (16), a region of the brain involved in certain forms of memory storage (21) The &scovery of hippocampal LTP provided direct experimental evidence for the existence of a form of physiological plasticity that fulfills several criteria of memory operation. LTP is a rapid and long-lasting increase in synaptic efficacy elicited by very brief episodes of high-frequency stimulation of excitatory pathways in hippocampal and other cortical clrcmts (15, 51, 99). Besides stability and rapid appearance, LTP exhibits other properties required for a memory mechanism, including synaptic specificity, dependency on neuronal firing patterns, and more importantly, assoclatlvity which is a sahent characteristic of memory systems (38,65). It should be noted that the LTP phenomenon is probably more complex than originally thought. First, multiple forms of potentiation ( " L T P j " and "LTP2") have been demonstrated In various limblc structures. These two forms of LTP decline steadily with two different half-times and thus could have different cellular substrates (99). Second, the mechanisms underlying LTP in areas CA1 and CA3 of hippocampus are likely to be different (39, 90, 113, 125). Finally, the relationships between different forms of LTP elicited by high-frequency stimulation of different neural pathways with multiple forms of memory remain to be elucidated. Neverthe- less, many theorists assume that the mechamsms underlying LTP could be similar or identical to those underlying learning processes and their studies have provided useful tools for the understanding of memory processes. The present review is concerned

415

416 MASSICOTTE AND BAUDRY

with the cellular triggers and substrates producing LTP m hlppocampal synapses. The first part explores the sequence of steps that appear to be necessary to reduce LTP. We will then de- scribe secondary enzymatic processes hypothesized to produce the permanent substrates of LTP, The final section will address questions concerning the relationships of LTP with learning and memory processes

TRIGGERING PROCESSES FOR LTP

NMDA Receptor Activatton

Pyramidal cells frequently fire m short bursts (3--4 pulses) at high frequency (100-4130 Hz) with the bursts repeated at the theta rhythm frequency (5-7 Hz), the major hippocampal EEG pattern m rats engaged m exploratory behavior (31, 100, 120). Using high frequency (100 Hz) electrical stimulation of the Schaffer-collateral pathway, ~t was found that the maximal and most reliable LTP was ehc~ted when the bursts were separated by 200 ms (~ e , bursts were dehvered at a 5 Hz frequency) (50) Stimulauon of the input pathways generates m target cells both EPSPs and IPSPs due to the existence of feed-forward inhibitory mterneurons. The IPSPs generally truncate the EPSPs and prevent their temporal summation dunng the course of brief bursts of presynaptic activity. These IPSPs are considerably reduced between 100 ms to about 1 s after a first stimulation to the same inputs or to inputs presumably activating the same set of inter- neurons. This phenomenon "pr imes" the pyramidal cell in such a way that a second stimulation of the same or different inputs to the cell w~th a brief burst results in a temporal summation of EPSPs (48-50) This summation produces a very large depolarization of the postsynaptlc membrane, which has a profound effect on the functional properties of a subtype of receptors for the neurotransm~tter released dunng the bursts of stimulation (49) These are the N-methyl-D-aspartate (NMDA) receptors, a subtype of glutamate receptors which are associated with an ion channel that ~s blocked by magnesium at resting membrane po- tentml (76,89). The temporal summation of EPSPs occumng dunng the short high-frequency bursts of electrical stimulation brings the membrane potential to a level where Mg + + does not block the NMDA receptor channels, thereby allowing then- func- tional activation. Selective antagonists of NMDA receptors, such as ammo-2-phosphonopentanoate (AP-5), do not interfere w~th the "pr iming" event, reduce the temporal summation of EPSPs m primed neurons (49) and prevent the reduction of LTP, at least m the CAI region and dentate gyrus of hlppocampus (24, 39, 49, 81).

The Glycme Site and LTP

A glycme site is associated with the NMDA receptors and its occupation by agomsts increases the probability of opening the NMDA receptor channel (42). Whether the glycine site is fully saturated under normal con&tlons m vwo or in v~tro still remains a controversml issue. Thts is because glyclne, or its analogue D-senne, produced little or no potentiation of the response of cells to NMDA, m slices. However, it has been reported that glycme potentiates NMDA receptor-medmted responses m neo- cortex and thalamus (117), two regions m which marked enhancement by glycine of glutamate binding has been reported (78). Kynurenate, a tryptophan metabohte which antagomzes excitatory amino acid responses, binds with h~gh-affimty to the glycine site associated with the NMDA receptor (46) The derivative 7-chlorokynurenic acid, a more selective and potent glycme antagomst, has recently been reported to prevent LTP induction m the CAI region of rat hlppocampal slices (6, 93,

94). The drug depressed both the NMDA receptor-medmted component of synaptlc transmission recorded In Mg z+-free medium and the Induction of LTP m Mg2+-contammg medium. These effects were also reversed by D-serlne, a glycine agonist, suggesting a direct action of the inhibitor at the allosterlc glycine site of the NMDA receptor. Finally, data obtained from 14- day-old cultures of hlppocampal neurons indicated that the increase in intracellular calcium produced by NMDA is also completely blocked by chlorokynurenic acid (95)

In addition, glycine has been reported to enhance NMDA- displaceable 3H-glutamate binding Using autora&ographlc tech- tuques, Monaghan et al (78) noted that the relative binding of 3H-CPP (an antagonist) versus 3H-glutamate (an agomst) to the NMDA receptor varies across brain regions and that the degree of stimulation of glutamate binding by glycme covanes with the binding of 3H-CPP. They proposed that this effect was due to the existence of two different populations of NMDA-blndmg sites, termed agomst-preferring and antagonist-prefemng and that glycme caused a conversion of NMDA receptors from a state that is relatively unresponsive to glutamate (antagonist-preferring conformation) to a conformaUon highly responsive (ago- rest-preferring). The NMDA receptor heterogeneity could be due to various posttranslat~onal mechanisms, such as phosphoryla- t~on, glycosdation, etc. or to different lipid mlcroenvironment of the receptors. We have recently observed that phospholipid al- teration of telencephahc membranes by phosphohpase C treatment ~s accompanied by a marked decrease m the binding of 3H-CPP and by a suppression of the stimulation by glyclne of 3H-glutamate binding (73) However, the binding of 3H-glutamate and 3H-glycme to the NMDA receptor was not modified by the same treatment, suggesting that alterations m the hpld m~croenvn-onment specifically modulate the antagonist-preferring conformation of the NMDA receptor Because the phospholipid composition of membranes, as well as their turn-over rates, can be modified under a number of physiological (17,87) and patho- logical conditions (18, 85, 104), it is possible that these conditions are associated with alterations in NMDA receptor function and therefore m synaptic operations.

Role of Calctum m LTP hlduction

Several lines of evidence indicate that Ca 2 ÷ influx triggers a cascade of biochemical events in the postsynaptlc structures that leads to the expression of LTP (62,68). For example, Lynch et al. (62) showed that intracellular injection of the calcmm chela- tor EGTA m CA1 pyramidal cells &d not result in alterations of synaptlc responses induced by the electrical stimulation of the Schaffer-commlssural pathway (except for the suppression of the Ca 2 + -dependent hyperpolarlzatlon that normally follows the EPSP) but totally prevented the formation of LTP. Calcium presumably enters the postsynaptlc elements through two different pathways, i e , voltage-gated channels and NMDA receptor channels (66). Calcium-imaging techniques have shown that large increases in lntracellular calcium take place in CA I pyramidal cells followmg high-frequency stimulation of the Schaffer-collateral system as a result of the activation of both types of channels (101) However, calcium entry through NMDA channels is determined by the dlsmbutlon of the receptors as well as by the dual re- qun-ement for then- actwatlon while Ca -'+ entry through the voltage-gated Ca 2+ channel depends on then" regional &stribu- tlon on neuronal membranes. It is interesting to note that NMDA receptors are widely &stnbuted in telencephalic structures but are virtually absent in nontelencephahc areas, a finding with clear ~mphcat~ons concerning the operations of excttatory synapses. Calcium entry through the NMDA receptors channel

HIPPOCAMPAL SYNAPTIC PLASTICITY 417

could thus produce a local increase in lntracellular calcium con- centratlon selectively at synapses which experience both postsynaptic depolarization and presynaptic release of neurotransmltter.

These findings suggest that the following sequence of events is necessary for inducing LTP m CA1 and dentate gyrus 1) bursts of electrical stimulation mlm~clong the theta rhythm induce a transient reduction in feed-forward IPSPs, thereby -prim- ing" CAI neurons, 2) subsequent bursts converging on neurons in the " p n m e d " state generate large depolarizations bnngmg their membrane potentials to a level where NMDA receptor channels are released from the magnesium blockade and become functionally activated; 3) Activation of the NMDA receptors and of the glycine site associated with them results in large increases in calcium concentration m the postsynaptic structures associated with the stimulated synapses. Thus, the selective increase in m- tracellular calcium is likely to represent the critical second messenger revolved in tnggering LTP and the initial sets of events m the postsynaptlc structure leading to long-lasting potentiation of synaptlc transmission.

POTENTIAL MECHANISMS FOR LTP MAINTENANCE

The properties of the NMDA receptors provide a powerful mechanism that links receptor activation w~th regulation of intracellular calcium It is clear that a transient rise in calcium concentration in postsynaptlc elements is likely to stimulate various calcium-dependent processes that could produce either short-lasting or long-lasting modifications of synaptic function Phosphorylatlon reactions for example have been widely discussed as ideal candidates for ehcIting short-lasting modifications of synaptlc function (43). The synaptlc complex possesses a full set of the different types of protein kinases [cychc AMP dependent, calcmm/calmoduhn dependent, especially the type II (Cam-KII) and calcium-dependent/phosphohpid-dependent kinase (Klnase C)], which have been shown to phosphorylate a wide range of synaptlc proteins, including possibly ionic channels and transmitter receptors. Longer-lasting modifications of synaptic function following transient changes in intracellular calcmm con- centratlons could also be provided by irreversible alterations of lipids or proteins, for example, calcium-dependent phospholl- pases could potentially perturb the lipid domain of the membrane sufficiently to modify proteln-hpld interactions, thus resulting m long-lasting alterations m cell surface receptors distribution and/or function. Calcium-dependent proteases are also attractive candidates for a mechanism translating brief changes in calcium concentrations into long-lasting and possibly permanent changes in synapt~c structure and operation.

Synaptlc responses in the hippocampus involve two subtypes of excitatory amino acid receptors, the NMDA and the non- NMDA, presumably of the AMPA/qulsqualate (A/Q) subtype receptors (25, 83, 84). The normal fast synaptic response produced by low frequency stimulation is mediated by the A/Q receptors. The modifications underlying LTP maintenance probably involve an increase in the components of the synaptic response mediated by the A/Q receptor without changes in those produced by the NMDA receptors (27, 45, 83) Davies et al. (27) de- scnbed an increased postsynaptic response to exogenously ap- plied qulsqualate 20 to 30 minutes after high-frequency stamulation This finding, however, contrasts with the studies of Muller et al. (83) showing a more rapid postsynaptic increase in responses medmted by the A/Q receptor. Nevertheless, it IS thus possible to hypothesize that the activation of Ca 2 ÷-dependent processes increases the postsynaptic responsiveness of the A/Q receptor through receptor and/or structural changes. This idea does not exclude the possibility that LTP is accompanied by presynaptlc

modifications [see (16) for a review]. Moreover, this possibility has been recently revitalized by results obtained using quantal analysis of synaptlc transmission before and after LTP. How- ever, while Malinow and Tsien (71) and Bekkers and Stevens (10) observed an increase in quantal content, Foster and Mc- Naughton (35) found that LTP was associated with an increase in quantal size. Some of the difficulties and problems raised by these results as well as more general comments concerning the presynaptlc versus postsynaptlc localization of the changes underlying LTP maintenance have been discussed elsewhere (60) The evidence supporting the role of different Ca-dependent enzymatic processes in the long-lasting changes in synaptlc efficacy that follow high-frequency stimulation will be discussed below.

Protein Kmases

Changes in phosphorylatlon of various proteins have been observed following high-frequency stimulation and it has been suggested that presynaptlc as well as postsynaptlc protein klnase activity is required for LTP (1, 5, 41, 67, 70). Additional support for a critical role for kmases in LTP comes from studies showing that protein kmase inhibltors such as polymyxin B and compound H-7 and different calmoduhn antagonists interfere with the formation of LTP (23, 57, 67, 70, 102) Furthermore, phorbol esters, which directly activate protein kinase C, produce a long-lasting increase in synaptlc transmission and it has been proposed that klnase C translocatlon and activation are important steps for LTP expression (1, 41, 69, 70). However, recent evidence indicate that the phorbol ester-induced potentiation (at least in CA1) is quite different from the LTP induced by high- frequency stimulation and do not support the hypothesis that activation of protein kinase C is involved in LTP maintenance (37,82). At present the role of protein kmase C in LTP remains therefore a controversial issue Calclum/calmoduhn-dependent protein kinase II appears to be a plausible candidate to participate in LTP. Biochemical studies have demonstrated that this kanase undergoes autophosphorylatlon, which could provide a self-perpetuating change in enzyme activity (55,77) It has been suggested that the ability of self-maintaining autophosphorylation of the Cam-KIl may serve as a mechanism for maintaining long-term changes in synaptic efficacy (36). The Cam-KII is a major protein component of the postsynaptlc densities and would be ideally localized to modify the properties and functions of postsynaptlc A/Q receptor. In good agreement with this idea, lntracellular injection of Cam-KII inhlbltors blocks LTP formation (67)

Lipases and Proteases

It seems a priori logical to explore those calcium-dependent processes likely to produce irreversible alterations in the structure and function of dendritic spines when searching for potential LTP-related mechanisms. Among these, the activation by calcium of calcium-dependent lipases (phosphohpases C and A 2) and neutral proteases (calpalns) are particularly attractive since the modifications produced by these enzymes are more likely to be irreversible, inasmuch as structural modifications should be more resistant to molecular turn-over than posttranslational modifications Activation of membrane-associated phospholipases rep- resents an important component of the effects of both neurotransmitters and hormones. By cleaving membranes phos- pholipids, these enzymes not only generate a number of metabohtes that can play a second messenger function reside or outside the cell, but also modify the lipid mlcroenvlronment of mem-


brane proteins Treatment of membranes with exogenous phosphohpases has been reported to alter the characteristics of the binding sites for various neurotransmitters or neuromodulators, such as norepinephrme (53,97), GABA (119) and the opioid peptldes (86,96). In a number of cases it was shown that the nonpolar or polar moieties of membranes phosphollplds, as well as the lysophosphohplds and fatty acids generated by phosphohpase treatment, were responsthle for the changes in receptor binding. In other cases ~t appears more hkely that changes in the hpld mlcroenvironment of the receptors produce alterations in the conformation of the receptor leading to changes in receptor binding (56). Recent reports have suggested the existence of hnks between excitatory amino acid receptors and phosphohpld lnetabohtes generated by either phosphohpases C or A~ (7, 30, 85, 87, 88). Stimulation of the NMDA receptors in primary cultures of neurons has been reported to produce an mcreased release of arachidonic acid, an effect that is likely due to the activation of endogenous phosphohpase A 2, a calcium sens~txve enzyme (30) Support for a critical role for phosphohpase A2 in LTP comes from studies showing that lnhlbltors of the enzyme interfere with the formation of LTP (54, 63, 74, 122, 123) However, whether the PLA n lnh~b~tors act on events responsible for the reduction of LTP such as transmatter release, NMDA receptor activation and Ca 2+ influx, or on processes subserving the maintenance of LTP has not always been well established Bliss and his colleagues have proposed that arach|donlc acid or some other phosphohpld derivative is released postsynaptically and acts as a retrograde messenger at the presynapt~c terminal, providing a hnk between the postsynapt~c location of the induction process and the presynaptlc locus for the maintenance mechamsm (14,15) They also reported that the hpoxygenase/ PLA~ mhxb~tor, nordihydroguaiaret~c acid (NDGA), blocks the formation of LTP and they proposed that a continuing release of hpoxygenase-denved arach~domc acid metabohtes is required for the expression of LTP (124). However, the drug has obvious effects on the physiological properties of the preparat|on, and tn particular it decreases the slope of the field EPSPs evoked by the stimulation of the Schaffer-collateral system. Apphcatton of BPB (bromophenacyl bromide; 50 p.M), a more specific phosphohpase A2 inhibitor, caused also a large reduction in the mag- mtude of LTP in field CAI of the h~ppocampal shce preparation The drug had, however, no s~gmficant effect on either the degree of paired-pulse faclhtat~on or on the amount of preestab- lished LTP, suggesting that phosphohpase A n activation plays a critical role in the development of LTP, but is not required for the maintenance of LTP (74)

As mentioned above, LTP is expressed by a selective increase in synaptlc currents me&ated by the AMPA/qu~squalate subtype of glutamate receptors How could PLA n activation produce the selective changes m responsiveness of the AMPA/quisqualate subtype of glutamate receptors observed in LTP? One possible explanation could be that PLA 2 activation reduces a se- lectwe modification of the binding and/or biophysical properties (such as changes in the conductance state of the channel) of the AMPA/qulsqualate, but not of the NMDA receptor-lonophore complex. In this regard it is of interest that treatment of telencephahc membranes w~th exogenous phospholipases (PLC and PLAn) produced a marked increase in the affinity of the A/Q receptor for the radlohgand 3H-AMPA (3H-ammo-3-hydroxy-5- methyhsoxazole-4-proplomc acid), without changing the binding properties of agomsts for the NMDA receptor complex, this effect is probably due to a PLAz-lnduced dmturbance m the hpld environment of the receptor (72,73) The functional conse- quences of th~s effect remain to be estabhshed, but it is hkely that it would Increase the physiological responses associated with A/Q receptors. Thus, st~mulatxon of NMDA receptors has been

linked to PLA n actlvat~on, which in turn reproduced a correlate of LTP (differential effect on A/Q and NMDA receptors). Fur- thermore, PLA 2 inhlbltors interfere with the development of LTP, an effect consistent with the hypothesis that PLA n partici- pates in the development of LTP, at least in field CAl of the hlppocampus We have recently reported that induction of sei- zure activity as a result of systemic kalnlC acid administration produced a loss of LTP m field CAI of hlppocampal shces (75). The loss of LTP did not appear to be due to major alterations in the physiological characteristics of the NMDA receptors, but was more hkely the result of the &sruptlon by kainate treatment of postsynaptlc processes which normally follow the activation of the ~onlc currents that are the lmtlal triggers for LTP Interest- Ingly, the PLA~-mduced increase in 3H-AMPA binding to the A/Q receptors was also markedly reduced in the hlppocampus after kalnate treatment. It is thus reasonable to assume that PLA2-1nduced modification of the A/Q receptor could represent a critical step for LTP maintenance This assumption is supported by recent results indicating that the PLA2-1nduced increase in 3H-AMPA binding is also absent in membranes prepared from neonatal rats at a developmental stage when LTP is not induced by high-frequency stimulation (9a). Thus, calcium-dependent phosphohpases are very attractive candidates for a mechamsm to translate brief changes in calcium concentrations into long-lasting and possibly permanent changes in synaptlc opera- tlon.

Calcium-dependent proteases have also been proposed to produce long-lasting changes in synaptlc structure and function (58, 59, 61) Two forms of this category of enzymes have been identified (calpain I and II) in the brain, which differ in their sensitivity to calcium. Calpam I is activated by mlcromolar con- centratlon of Ca 2+, and its locahzatlon m dendritic spines and postsynapt~c densities has been confirmed by ~mmunohlstochem- lcal techniques (98). Substrates of this protease include protein kinase C and various proteins constituting the cell cytoskeleton such as, neurofilament proteins, mlcrotubule-assoclated proteins, tubuhn, actm and brain spectrin [see (8) for a review]. Interest- mgly, spectnn has been proposed to be involved m the regulation of the &stnbution of cell surface receptors in a variety of cells In particular, spectnn has been shown to participate m the capping of cell surface receptors (52), and it was recently proposed that calpam-lnduced degradation of spectrm-hke proteins is responsible for the uncovenng of fibnnogen receptors m blood platelets stimulated by thrombin or ADP (4) Electron micro- scopic studies have shown that morphological changes m postsynaptlc sprees and/or synapses are assocmted with LTP (3, 19, 33, 34, 122) However, several results suggest that structural mo&ficatlons per se are not likely to produce long-lasting mo&ficatlons of synaptlc transmission (40,105). Given that LTP is both synapse-specific and Ca 2 +-dependent, and given the nature of calpam substrates, it was postulated that calpam is revolved m these ultrastructural modifications (59) In addition, activation of NMDA receptors, a necessary condition for inducing LTP in CAI, produced a rapid stimulation of calpain, as re- flected by the accumulation of spectnn breakdown products (106) It is of interest that leupeptin and more specific calpam antagonists (calpain inhibitor I and II) also block the formation of LTP, without markedly &srupting the physiological events that normally induce the potentiation effect (28, 92, l 1 I). There is ample evidence to support the notion that the inner leaflet of the lipid bllayer membrane of most eukaryotlc cells is rich m phosphatldylserme (PS), an ammophosphohpld. In contrast, the outer leaflet of the membrane hpld bllayer contains virtually no PS (126). Recent results indicated that the asymmetric orientation of PS ~s due to the existence of an aminophosphohpid translocase activity m the plasma membrane, which is inactive dunng calpain

HIPPOCAMPAL SYNAPTIC PLASTICITY 419

acuvat~on (26). In platelets, tt has been shown that increased surface exposure of PS (flip-flop) ts rapidly observed upon activation by certain agents, an effect correlating with the extent of proteolyt~c degradation of the cytoskeletal protein spectnn (126). Recent stu&es have in&cated that the incorporation of PS in telencephahc membranes Increases the affinity of A/Q receptors, an effect similar to the PLA, treatment (9). These results suggest a new mechanism by which membrane reorganization and fhp-flop of phosphatldylsenne could combine to produce an increased affinity of the A/Q receptor that might provide maintenance of LTP.

Figure 1 summarizes these different points m a model de- scnbmg the means by which calcium may increase the affinity of A/Q receptors in synaptlc membranes We postulate that modification of the lipid microenvlronment by the Ca + +-dependent phospholipase A 2 may selectively modulate the affinity of the A/Q receptor and provide the maintenance of LTP. More- over, calpain and kinase activation represent addmonal mechanisms by which membrane reorganization, structural modifications and receptor alterations could become long lasting Interestingly, data obtained m our laboratory ln&cate that treatment of telencephalic membranes with calpam pamally blocks the modulation of A/Q receptors produced by phosphohpase Az, suggesting that the order of actwation of different CaZ+-dependent processes mxght be |mportant m determining the resulting changes m receptor propemes and functions (75) Further experiments are needed to evaluate the effects of different protein klnases on the properties of the A/Q receptors and/or their regulation by the lipid environment m the membranes.

Protein Synthesis and Gene Expression

It has also been proposed that biochemical changes at the level of protein synthesis and gene expression could be revolved in the maintenance of long-lasting changes m synaptic operation.

In the hippocampus, protein synthesis mhlbttors have been reported to interfere with both the induction and the maintenance of LTP (47,109). Furthermore, release of newly synthesized proteins mto the extracellular space has been shown to take place in area CAI and dentate gyrus of the hippocampus, following LTP induction by high-frequency stimulation (29,32). It appears now that polyribosomes are present in dendrites, often locahzed at the base of dendritic sprees (115). There exxsts therefore a posslblhty for local regulation m protein synthesis in response to certain types of synapttc activity Interestingly, h~gh-frequency st~mulatlon of presynapuc afferents results In an increase m the state of aggregation of polynbosomes (122) and it has been suggested that such stimulation results m the translation of specific mRNA coding for some subset of synaptic proteins (115). How- ever, little is known concerning the nature of the proteins lo- cally synthesized as well as of the intracellular signals responsible for the induction of protein synthesis.

Changes in phenotyp~c expression m response to a variety of factors such as hormones or prolonged depolarization represent another mechanism providing adaptatwe properties to synaptlc transmission (13,80). Stu&es in invertebrates have suggested that a rapid genomic response to neuronal stimulatmn plays a critical role m long-term changes m synaptlc efficacy (80). High-frequency stimulation of the perforant path-granule cell synapses m vivo, produced a marked increase m the amount of mRNA for one class of gene (Zif 268) that belongs to the category of immediate early genes (22). The increase in Zif 268 mRNA mduced by high-frequency stimulation was also blocked by NMDA receptors antagomsts. Because Zff 268 probably en- codes a transcription regulatory factor, it ~s possible that the rapid mcrease in Zif 268 could be important in coordlnatmg

Before LTP NMDA

Ca++

After LTP

NMDA

FIG 1 Schematic dmgram lllustratmg a putauve mechanism for LTP maintenance Before LTP, it is assumed that most of the phosphat~dyl- serlne (filled polar heads) m the llp~d bdayer is facing the reside of the cell, and the A/Q receptors exist m a state of low affinity for the transmitter Actlvanon of the NMDA receptors dunng the tnggenng phase results in an reflux of calcium in postsynaptlc structures and m the stimulation of a variety of calcmm-dependent enzymes, including PLA 2, calpam and kmases As a result, the &stnbunon of phosphohpldS m the hpld bdayer, and in pamcular that of phosphatldylsenne, is modified and the A/Q receptors are shifted m a state of h~gh affinity or of higher "re- sponsweness" for the transmitter

changes m gene expression that underlie long-term changes in synaptic efficacy. In summary, the posslbthty that actwlty-dependent mo&ficatlons in genomlc expression affecting the phe- notyplc characters of adult neurons adds an almost unhmited degree of adaptative propemes to synaptlc transmission. In particular, the recent cloning and detaded analys~s of cDNAs en- coding AMPA receptors have revealed the existence of a family of receptors Moreover each member of the family exists m two closely related versions generated by alternate sphcmg of the gene. They have been designated as " f l i p " and " f l o p " and as they exhibit different physiological responses to glutamate ago- rests, xt has been proposed that changes in the expression of AMPA receptors may play an important role in synaptlc plasticity (107)

RELATIONSHIPS BETWEEN LTP AND LEARNING AND MEMORY

One of the major issues in the neuroblology of learmng and memory remains the elucidatxon of the relationships between the cellular mechanisms of synaptlc plasticity and the behavioral


mamfestat~ons of learning and memory. Numerous studies have attempted to link LTP and the learning of spectfic behavioral tasks. Several lmes of evidence suggest that LTP ~s involved in behavioral learning and memory In classical conditioning [e.g , of the mct~tating membrane (NM) response], pyramidal neurons rapidly increase their frequency of d~scharges wtthin trtals, be- ginning m the first few trials, and form a predicting "temporal model" of the learned behavioral response (12). When the pop- ulatlon spike of dentate granule cells elicited by perforant path stimulation ~s monitored over the course of learning, ~t increases in parallel with the development of the learned behavioral response and this increase persists m time (121). Although the h~ppocampus ~s not essentml for basic associative learning (e.g., NM condmomng), ~t becomes essentml when greater demands are placed on the memory system, as m discrimination reversal of NM condmomng (116). When LTP of the perforant path ~s reduced m rabb~ts, subsequent acquisition of s~mple NM condt- tloning is accelerated (11) Th~s result ~s m apparent contradic- tion with a similar study m rats, where long-term potentiation reduced by high-frequency st~mulatton in the same pathway ~m- pmred the acqumit~on of a new spatial task, which ~s crittcally dependent on normal hippocampal function (64). The results were supporting the ~dea that previous induction of LTP maxi- mized synaptic efficacy, thus makmg it more difficult to modify the network for learning a new spatml task. In the p~r|form cortex, patterned electrtcal stimulations of the lateral olfactory cortex (LOT) can be used mstead of natural odors m smell discrimination learning experiments and learning of the d~scnm~- nation between a natural odor and the "electrical odor" is accompanied by an increase in the amphtude of the evoked potentmls generated by the electrical st.mulatton of the LOT (103). Exper- iments testing for modifications m receptor-binding propert|es followmg physiological act~vmes are m progress. Increase in 3H-AMPA binding has been obtamed m experiments using quan- titative autorad.ography following learning of a classtcal condi- tioned task m rabbtts (118). The same learning paradigm has also been shown to be accompanied with translocatton of pro- tern kmase C to the dendritic zones of field CA1 m h~ppocampus (9 I)

Another approach to estabhsh the relation between LTP and learning and memory has conststed m using pharmacological tools provided by the cellular analysts, tn order to evaluate the cQnsequences at the behavioral level of mterfenng with specific cellular mechantsms. Recent experiments have taken advantage of the selecttve blockade of LTP by NMDA receptor antagonists. Thus, rats receiving a continuous intraventncular infusion of AP-5 exh,b.ted a profound tmpairment in their ablhty to store both spatial (81) and olfactory (114) reformations [however, see Mondadorl et al. (79) for an alternative v~ew of the data]. Fur- thermore, and in agreement with the calpam/spectnn hypothesis described above, ~t was found that the mtraventncular mfuslon of the calpam inhth~tor leupeptm, also produced a marked lm- patrment in the learning of spatial and olfactory tnformat~on (110,111). For both AP-5 and leupeptin, the drug treatment d.d not tmpalr the learning of other types of information such as vt- sual discnmmatlon and shock avoidance. These results strongly suggest that LTP-like mechanisms specifically participate in the learning of olfactory and of spatml reformation

The effects of inhtbttors of protem kmases and of phosphohpases on the learning of different tasks remain to be tested but data from invertebrates certainly suggest that protein kinases at least are mvolved m the learning of some forms of information. No data are avadable yet on the possible involvement of phospholipases m learning and more specific mhib~tors are needed in order to test thetr participation m behavioral experiments. Ft- nally, learning of a vartety of tasks has been reported to be im- patred following the administration of protein synthests mhlbitors. These results clearly tnd~cate the urge for estabhshmg a taxon- omy of learning processes and for clarifying the roles of different classes of biochemical processes in learnmg and memory

ACKNOWLEDGEMENTS

Th,s work was supported by Grants BNS 89-96284 from the National Science Foundanon to M B G M ~s recipient of a Fellowship from the Fonds de ta Recherche en Sant6 du Qu6bec We w~sh to thank Clau- dine Jutras for her expert secretarial assistance

R E F E R E N C E S

1 Akers, R F , Lovmger, D M, Colley, P A , Linden, D J , Rounenberg, A Translocatlon of protem kmase C actwuy may medmte hlppocampal long-term potentmtlon Science 231 587-589, 1985

2 Alkon, D L Calcmm-medlated reduction of lomc currents a biophysical memory trace Science 226 1037-1045, 1984

3 Applegate, M D. Kerr. D S , Landfield. P W Redistribution of synapt~c vesicles dunng long-term potentmtton m the hlppocampus Brain Res 401 401--406. 1987

4 Baldassare, J , Bakshlan, S , Krupp, M A . Fisher. G J Inhibi- tion of fibnnogen receptor exposure and serotonm release by leupeptm and antlpam J Blol Chem 260 10531-10535, 1985

5 Bar, P R,Schotman, P,Glpsen, W H.Tlelen, A M, Lopes. K A , Sdva, F H Changes m synaptlc membranes phosphoryla- tmn after tetamc stimulation m the dentate area of the rat h~ppocampal shce Science 198 478-484, 1980

6 Bashlr, Z I , Tam, B , Colhngndge, G L Acttvatlon of the glycme site m the NMDA receptor as necessary for the mductton of LTP Neuroscl Lett 180261-266, 1990

7 Baudry. M , Evans, J , Lynch, G Excitatory ammo acids inhibit stimulation of phosphaudyhnosltol metabohsm by ammerglc ago- rests m h~ppocampus Nature 319 329-331, 1986.

8 Baudry, M, Lynch. G Properties and substates of mammahan memory systems In Meltzer, H Y, ed Psychopharmacology The third generation of progress New York Raven Press, 1987

9 Baudry, M. Mass~cotte, G , Hauge. S Phosphat~dylsenne m-

creases the affimty of the AMPA/qu~squalate receptor m rat brain membranes Behav Neural Blol 55 137-140, 1991

9a Baudry, M , Mass.cone, G , Hauge, S. Opposite effects of PLA 2 on aH-AMPA binding m adult and neonatal membranes. Dev Brain Res . m press, 1991

10 Bekkers, J M . Stevens, C F Presynaptlc mechamsm for long- term potentmtlon m the hlppocampus Nature 346 724-729, 1990.

II Berger, T W Long-term potentmtlon of hlppocampal synapt~c transm,sslon affects rate of behavioral learning Science 224 627- 630, 1984

12 Berger, T W, Thompson, R F ldenUficatlon of the pyramidal cells as the cnucal elements m h~ppocampal neuronal plast~cUy dunng learning Proc Natl Acad Scl USA 75 1572-1576. 1978.

13 Black, I B,Adler, J E,Dreygus, C F,Jonakau, G M.Katz, D. M , Lagamma, E F , Markey, K M Neurotransmlner plastic- Ity at the molecular level Science 225 1266-1270, 1984.

14 Bhss. T V P , Douglas, R M,Emngton, M L,Lynch, M A Correlation between long-term potentmt~on and release of endogenous amino ac,ds from dentate gyrus of anesthetized rats J Phys- iol (Lond) 337 391--408, 1986

15 Bhss, T V P , Lomo, T Long-lasting potentmtlon of synapt~c transm,ss~on m the dentate area of the anesthetize rabb.t following sumulat~on of the perforant path J Physlol 232 334-356, 1973

16 Bhss, T. V P , Lynch, M A Long-term potentmtxon mechamsms and propert,es In Landfield, P , Deadwyler, S , eds Long-term potentmt~on From b~ophys~cs to behavtor New York Alan,

H I P P O C A M P A L S Y N A P T I C P L A S T I C I T Y 421

Llss, 1988 17 Bum, R , Lazeyras, F , Aue, W. P ; Straehl, P , B~gler, P , AI-

thaus, U , Herschkow~tz, N Correlation between 31P NMR phos- phomonoester and b~ochem~cally determined phosphorylethanola- mine and phosphat~dylethanolamme dunng development of the rat brain Dev Neurosci 10213-221, 1988

18 Butterfield. D A , Markesbury, W R Spec.ficlty of b~ochem~cal and btophystcal alterations m erythrocyte membranes m neurologi- cal d~sorders J Neurol. Sc~ 47261-271, 1980

19 Chang, F . Greenough. W. T Transient and endunng morpholog)- cal correlates of synapt~c acttv~ty and efficacy change m the rat h~ppocampal shce Brain Res 309 35-46, 1984

20 Changeux, J P , Komsh~, M The neural and molecular bases of learning Dahlem Konferenzen, 1987

21. Cohen, N , Sqmre, L. R Preserved learning and retention of pattern-analyz|ng skill in amnesta D~ssocmt~on of knowmg how and knowing what Science 210 207-209. 1980

22 Cole, A J , S a f f e n , D W , B a r a b a n , J M , W o r l e y , P F Rap~d increase of an ~mmedmte early gene messenger RNA m htppocampal neurons by synapt~c NMDA receptor acttvatton Nature 340 474--476; 1989.

23 Colley, P A , Sheu, F S., Routtenberg, A Dose-dependent phorbol ester facd~tat~on or blockade of h~ppocampal long-term potent~- at)on- relation to membrane/cytosol d~stnbut~on of protein kmase C activity Brmn Res 495 205-216, 1989

24 Colhngndge. G L , Kehl. S J , McLennan, H The antagomsm of amino acid-induced excitations of rat h~ppocampal CAI neurones m v~tro J Phys~ol (Lond) 334(11 19-31, 1983.

25 Colhngndge, G L , Kehl, S J , McLennan, H Excitatory amino acids m synapt~c transmission m the Schaffer collateral-commlssural pathway of the rat h~ppocampus J Phys~ol (Lond.) 334(11 33---46, 1983

26 Comfunus, P , Senden, J M G .Tdly . R H J . Schro~t. A J . Bevers. E M . Zwaal. R F A Loss of membrane phosphohp~d asymmetry m platelets and red cells may be assocmted with calc)- urn-reduced shedding of plasma membrane and mh.bmon of am~- nophosphohp~d translocase. B~och)m B~ophys Acta 1026 153- 160. 1990

27 Davies. S N , Lester, R A . Reymann, K G ; Colhngndge. G L Temporally d~Stlnct pre- and post-synapt~c mechamsms mare- tam long-term potentmtlon. Nature 338 500-503. 1989

28 del Cerro. S . Larson, J , Ohver, M W . Lynch. G Development of h~ppocampal long-term potentmt~on ~s reduced by recently intro- duced calpam lnh~b~tors Brain Res 530 91-95, 1990

29 Duffy. C , Teyler, T J , Shashoua. V E Long-term potentat~on m the h~ppocampal shce ewdence for stimulated secretion of newly synthesized proteins Science 212 1148-1151. 1981

30 Dumu~s, A , Sebben, M , Haynes. L , Pro. J P , Bockaert, J NMDA receptors actwate the arach)don|c acid cascade system m stnatal neurons Nature 336.69-70, 1988

31 E~chenbaum, H.. Kuperstem, M . Fagan, A . Nagode. J Cue- samphng and goal-approach correlates of h~ppocampal umt act)v~ty m rats performing an odor-d~scnmlnat~on task J, Neurosc~ 7 716-- 732, 1987

32 Fazeh. M S., Ernngton, M L , Dolphin, A C , Bhss, T V Long-term potentmhon m the dentate gyrus of the anaesthetized rat is accompamed by an increase m protein efflux Into push-pull can- nula perfusates Brain Res 473(11:51-59, 1988

33 Fffkova, E Possthle mechamsm of morphometrlc changes in den- dnt~c sprees reduced by st~mulatton Cell Mol Neurob~ol 5 47- 63. 1985

34 Fffkova, E . vanHarreveld. A Long-lasting morphologtcal changes m dendritic sprees of dentate granule cells following sumulat)on of the entorhmal area Neurocytology 6:211-230. 1977

35 Foster, T C . McNaughton, B L Long-term synapuc enhancement m CAI ~s due to mcreased quantal size, not quantal content Hlppocampus 1 79-91, 1991

36 Fnednch, P Protein structure The primary substrate for memory Neurosc~ence 35 1-7, 1990

37 Gustafsson, B . Huang. Y Y., W~gstrom, H Phorbol ester-reduced potentmtton differs from long-term potentmt~on m the gum- ea-p~g h~ppocampus m vitro Neurosc~ Lett 85 77-81. 1988

38 Gustafsson, B , Wlgstrom, H Physlologacal mechamsms underly-

mg long-term potentiation Trends Neuroscl 12 92-97; 1989 39 Hams. E W , Cotman, C W Long-term potentiation of guinea

pig mossy fiber responses is not blocked by N-methyl-D-aspartate receptor antagomsts. Neuroscl Lett 70 132-137. 1986

40 Hams, K M . Stevens, J K Dendritic spmes of CA I pyramidal cells m the rat hlppocampus" Serial electron microscopy with ref- erence to their biophysical characteristics J Neurosc~ 9 2982- 2997, 1989

41 Hu, G Y , H v a l b y , O , W a l a a s , S l ,AIber t , K A,Sk je f lo , P , Andersen, P , Greengard. P. Protein kmase C rejection into h~ppocampal pyramidal cells ehc~ts features of long term potentiation Nature 328 426--429, 1987

42 Johnson, J. W . Ascher, P Glycme potentiates the NMDA response m cultured mouse brain neurons Nature 325529-531, 1987

43 Kandel, E R , Schwartz, J H , Castelluccl. V F , Schacher, S , Goelet, P Some pnnc~ples emergmg from the study of short- and long-term memory Neurosct, Res 3 498-520, 1986

44 Kandel, E R , Schwartz. J H Molecular Biology of learmng Modulat.on of transmitter release Sc.ence 218 433--443. 1982

45 Kauer, J A., Malenka, R C . N~coll, R A A perststent postsyn- apttc modification mediates long-term potenttatlon m the htppocampus Neuron 1911-917, 1988

46 Kessler, M , Terramam, T , Lynch, G , Baudry, M A glycme site assocmted w~th N-methyl-D-asparhc Acid receptors characteriza- tion and ~dentlficatlon of a new class of antagomsts J Neurochem 52 1319-1328, 1989

47 Krug, M , Lossner. B , Ott. T Amsomycm blocks the late phase of long-term potentmt~on m the dentate gyrus of freely moving rats Sctence 13 39-42. 1984

48 Larson. J , Lynch, G Induction of synapttc potenttatton m hmppo- campus by patterned stimulation revolves two events Science 232 985-988, 1986

49 Larson. J , Lynch, G Role of N-methyl-D-aspartate receptors m the mduct~on of synaptic potenuat~on by burst st.mulat~on patterned after the h~ppocampal theta rhythm Brain Res 441 1 I I-I 18. 1988

50 Larson, J . Wong, D , Lynch, G Patterned stimulation at the theta frequency ~s optimal for mduct~on of long-term potentmt~on Brain Res 368 347-350, 1986

51 Lee, K S Sustained enhancement of evoked potentmls following brief, h~gh-frequency stimulation of the cerebral cortex m v~tro Brain Res 239 617-623. 1982

52 Levme, J . Willard, M Fodnn axonally transported polypeptldes associated with the internal periphery of many cells J Cell Blol 90(3) 631-642. 1981

53 Ltmblrd, L E , Letkow~tz, P J Adenylate cyclase-coupled beta- adrenerglc receptors effect of membrane-perturbing agents on receptor binding and enzyme stimulation by catecholammes Mol Pharmacol 12 559-567, 1976

54 Linden, D J , Sheu, F S , Murakamt, K , Routtenberg. A En- hancement of long-term potentmtlon by c~s-unsaturated fatty acid relation to protein kmase C and phosphohpase A~ J Neurosc~ 7(1 I) 3783-3792, 1987

55 L~sman. J E , Goldrmg, M A FeasJbdlty of long-term storage of graded reformation by the Ca + +/calmoduhn dependent protein klnase molecules of the post-synapUc density Proc Natl Acad Sc~ USA 83 5320-5324, 1988

56 Loh, H H . Law, P Y The role of membrane hplds m receptor mechamsms Annu. Rev Pharmacol Toxtcol, 20 210-234. 1980

57 Lovmger, D M., Wong, K L . Murakaml. K . Routtenberg. A Protein kmase C mhlbltors ehmmate hlppocampal long-term potentmtlon Brain Res 436(11 177-183, 1987

58 Lynch, G , Baudry. M. The bmchemlcal bas~s of learning and memory a new and specific hypothesis Sctence 224 1057-1063. 1984

59 Lynch, G , Baudry, M Brain spectnn, calpam and long-term changes m synaptlc efficacy Brain Res Bull 18 809-815. 1987

60 Lynch, G , Baudry, M Re-evaluating the constraints on hypothe- s.s regarding LTP expression Hippocampus, m press, 1991

61 Lynch, G , Larson, J . Baudry, M Treatment development strate- gies for Alzhe~mer's d~sease Madison Mark Powley Assoc 1986 119-139

62 Lynch, G , Larson. J , Kelso, S , Barnonuevo, G , Schottler, F


Intracellular injections of EGTA block mduction of hippocampal long-term potentiation. Nature 305 20-26, 1983

63 Lynch, M A , Ernngton, M L., Bhss, T V Nordthydrogual- aretlc acid blocks the synaptic component of long-term potentmtion and the assocmted mcreases m release of glutamate and arachldonate an m vivo study m the dentate gyrus of the rat Neu- rosclence 30(3) 693-701, 1989

64 McNaughton, B L , Barnes, C A , Rao, G , Baldwin, J , Ras- mussen, M Long-term enhancement of h~ppocampal synaptlc transmission and the acquisition of spatial mformat~on J Neurosc~ 6 563-571. 1986

65 McNaughton. B L , Douglas, R M , Goddard, G. V Synaptic enhancement of fascia dentate Co-operatlvity among coactwe afferents. Brmn Res 157 277-293; 1978

66 MacDermott, A B . Dale, N Receptors, ion channels and synap- tac potentmls underlying the integrative actions of excitatory amino acids Trends Neuroscl 10 280-283, 1987

67 Malenka, R. C.,Kauer, J A,PerkeI, D J ,Mauk , M D,Kel ly , P T , Nlcoll, R A , Waxham, M N An essential role for postsynaptic calmoduhn and protem klnase activity m long-term potentmUon Nature 340 554-557, 1989

68 Malenka, R C , Kauer, J A , Zucker, R S , Nlcoll, R A Postsynaptic calcium Is sufficient for potentiation of hlppocampal synaptlc transmiss~on Science 242"81-84, 1988

69 Malenka, R C , Madison, D B , Nlcoll, R. A Potentmtion of synapttc transmlssion m the htppocampus by phorbol esters Na- ture 321 175-177, 1986

70 Mahnow, R , Madison, D V , Tsien, R W Persistent protein klnase activity underlying long-term potentiation Nature 335 820- 824, 1988.

71 Mahnow, R , Ts~en, R W Presynaptic enhancement shown by whole-cell recordings of long-term potentmtion in hippocampal shces Nature 346 177-180, 1990

72 Massicotte. G , Baudry, M. Modulation of AMPA/qulsqualate receptors by phosphohpase A, treatment Neurosci Lett 118245- 249, 1990

73 Mass~cotte, G , Kessler, M , Lynch, G , Baudry, M N-methyl-D- aspartate and quisqualate/Ampa receptors Differentml regulation by phosphohpase C treatment Mol Pharmacol 32 278-285, 1990

74 Massicotte, G , Oliver, M W . Lynch, G , Baudry, M Effect of bromophenacylbromlde, a phosphohpase A~ inhibitor, on the reduction and maintenance of LTP m h~ppocampal slices Brain Res 537 49-53, 1990

75 Massicotte. G , Vanderkhsh, P , Lynch, G , Baudry. M Modula- tion of AMPA/qmsqualate receptors by phosphohpase A,,. a necessary step m long-term potenuation Proc Natl Acad. Sct USA 88 1893-1897, 1991

76 Mayer, M L , Westbrook, G L , Guthne, P B Voltage-dependent block by Mg ÷ + of NMDA responses m spinal cord neurones Nature 309 261-263, 1984

77 M~ller, S G . Kennedy, M B Regulation of brain type 11 Ca+ + /calmoduhn-dependent protein kmase by autophosphorylat~on A Ca + + triggered molecular sw~tch Cell 44 861-870. 1986

78 Monaghan, D T , Olverman. H J , Nguyen, L , Watkms, J C , Cotman, C W Two classes of N-methyl-D-aspartate recogmt~on s~tes differential distribution and differentml regulation by glycme Proc Natl Acad Scl USA 859836-9840, 1988

79 Mondadon, C , Weiskrantz, L , Buerkl, H , Petschke. F , Fagg. G E NMDA receptor antagonists can enhance or impair learning performance m animals Exp Brain Res 75 449-456, 1989

80 Montarolo, P G , Goelet. P , Castellucl, V F , Morgan, J., Kan- del, E R , Schacher, S A critical period for macromolecular syn- thes~s m long-term heterosynaptic facilitation m Aplysm Science 234 1249-1254, 1986

81 Morns, R G M , Anderson, E , Lynch, G S , Baudry, M Se- lective impairment of learning and blockade of long-term potentmtlon by the N-methyl-D-aspartate receptor antagonist, AP-5 Nature 319 774-776, 1986

82 Muller, D , Buchs, P - A , Dunant, Y , Lynch, G Protein kmase C acuvity is not responsible for the expression of long-term poten- tiat~on in h~ppocampus Proc Natl Acad Sct USA 87 4073- 4077, 1990

83 Muller, D , Joly. M , Lynch, G Contributions of qmsqualate and

NMDA receptors to the reduction and expression of LTP Science 242(4886) 1694-1697, 1988

84 Muller, D . Lynch, G Synaptlc modulation of N-methyl-D-aspartate receptor mediated responses m hlppocampus Synapse 5 94- 103, 1990

85 Nakagawa, Y , Baudry, M Dissociation between changes m glutamate receptor binding s~tes and their couphng to phosphatldyh- nosttol metabohsm following mtrahlppocampal colchlcme mjectlon Neurosclence 32 363-369, 1989

86 Nakajima, M , Taguch~, R . Ikezawa, H Effects of phosphohpases C from bacteria on binding of enkephahn to rat brain membranes. Toxlcon 25 555-564, 1987

87 Nlcolettt, F , Iadarola, J. J . Wroblewska, J T , Costa, E Excita- tory amino acid recogmtlon s~tes coupled with mosltol phosphohp~d metabolism, developmental changes and interaction with o~-adrenoreceptors Proc. Natl Acad Sc~ USA 83 1931-1935. 1986

88 Nlcolettl. F., Wroblewskl, J T , Alho, H , Eva, C , Fadda, E , Costa, E Lesions of putative glutamaterg~c pathways potentiate the increase of mositol phosphohpld hydrolysis elicited by excitatory amino acids Brain Res 436(11 103-112, 1987

89 Nowack, L , Bregestovsk~, P , Ascher, P , Herbert, A , Prochmntz, A Magnesium gates glutamate-activated channels m mouse central neurones Nature 307 462-465, 1984

90 Okada, D , Yamaglshl, S., Sugiyama, H Differential effects of phosphohpase mhtbitors m long-term potentmt~on m the rat htppocampal mossy fiber synapses and Schaffer/commissural synapses Neuroscl Lett 100(I) 1-3, 1989

91 Olds, J L . Anderson, M L , McPh~e, D. L . Staten, L D , Alkon, D L Imaging of memory-specific changes m the distribution of protein kmase C m the hippocampus Science 245 866--869, 1989

92 Ohver. M W , Baudry, M., Lynch, G The protease inhibitor leupeptm interferes w~th the development of LTP m hlppocampal slices Brain Res. 505 233-238, 1989

93 Ohver, M W , Kessler. M , Larson. J , Schottler, F , Lynch, G Glycine site associated with the NMDA receptor modulates long- term potentmtion Synapse 5 265-270, 1990

94 Ohver, M W , Larson, J , Lynch, G Activation of the glycme s~te assocmted with the NMDA receptor is required for reduction of LTP m neonatal h~ppocampus Int J Dev Neuroscl., m press, 1990

95 Oliver, M. W , Shacklock, J A , Kessler, M , Lynch, G , Balm- bridge, K G The glycme site modulates NMDA-medlated changes m mtracellular free calcium m cultures of hlppocampal neurons Neucoscl Lett 114 197-202, 1990

96 Pasternak, G. W., Snyder, S H Opmte receptor binding enzymatic treatments d~scnmmate between agomst and antagonist interactions. Mol Pharmacol 10 183-193, 1974

97 Penyasamy. S , Somam, P Effect of proteases and phosphohpases on 3H-yohimbme binding to human platelet membranes Biochem Pharmacol 35 3131-3136, 1986

98 Perlmutter, L S , Slman, R , Gall, C . Seubert, P , Baudry, M , Lynch, G The ultrastructural locahzat~on of calc~um-acuvated protease "calpain'" m rat brain Synapse 2 79-88. 1988

99 Racme, R J , Milgram, N W , Hafner, S Long-term potentiation phenomena m the rat hmblc forebram Brain Res 260(21 217-231, 1983

100 Ranck, J B J Studies on single neurons m dorsal hlppocampal formation and septum in unrestrained rats Exp Neurol 41.462- 531, 1973

101 Regehr, W G , Connor. J A , Tank, D W Optical imaging of calcium accumulation m hippocampal pyramidal cells during synaptic activation Nature 341 533-536, 1989

102 Reymann, K G , Frey, U , Jork, R , Matthtes, H. Polymixm B, and inhibitor of protein kmase C, prevents the maintenance of synapt~c long-term potentiation m h.ppocampal CAI neurons Brain Res 440 305-314, 1988

103 Roman. F , Staubh, U . Lynch, G Evidence for synaptlc potentiation in a cortical network dunng learnmg Brain Res 418 221-226, 1987

104 Rotrosen, J , Wolkm, A Phosphohpld and prostaglandm hypothe- ses of schlzophrema In: Meltzer, H Y.. ed Psychopharmacolo-

H I P P O C A M P A L S Y N A P T I C P L A S T I C I T Y 423

gy" The third generation of progress. New York Raven Press, 1987

105. Schottler, F. The nature and role of structural changes In long-term potentmuon. Ph D Thesis, UC Irvtne, 1990

106 Seubert, P , Larson, J , Oliver, M.; Jung, M. W , Baudry, M., Lynch, G Stimulation of NMDA receptors reduces proteolysts of spectnn in hlppocampus Brain Res 460.189-194, 1988.

107. Sommer, B , Kelnanen, K.; Verdoorn, T A , Wlsden, W.; Burna- shev, N , Herb, A., Kohler, M., Takagl, T , Sakmann, B , See- burg, P. H Flip and flop' a cell-specific functional switch in glutamate-operated channels of the CNS Science 249.1580-1585; 1990

108 Squire, L R. Mechamsms of memory Science 232 1612-1619, 1986

109 Stanton, P K., Sarvey, J. M Blockade of long-term potentiation in rat hlppocampal CA1 region by mhlbltors of protein synthesis. J. Neuroscl 4 3080-3088, 1984

I10 Staubll, U , Baudry, M , Lynch, G Leupeptln, a thlol-protemase inhibitor, causes a selective impairment of maze performance in rats Behav Neural Blol 40 58-69, 1984

111. Staubh, U., Baudry, M , Lynch, G. Olfactory discrimination learn- lng is blocked by leupeptln, a thlol protease inhibitor. Brain Res 337 333-336; 1985

112. Staubh, U , Larson, J , Baudry, M , Thlbault, O., Lynch, G Chronic adnunlstratlon of a thlol-protemase inhibitor blocks long- term potentmtlon of synaptlc responses Brain Res 444 153-158, 1988

113 Staubh, U , Larson, J., Lynch, G Mossy fiber potentiation and long-term potentiation involve different expression mechanisms Synapse 5:333-335; 1990

114 Staubh, U , Thlbault, O , DiLorenzo, M., Lynch, G. Antagonism of NMDA receptors impairs acquisition but not retention of olfactory memory. Behav Neuroscl. 103.54--60; 1989

115 Steward, O., Levy, W. B Preferential localization of polynbosomes under the base cells of dentate gyrus J Neuroscl. 2.284-- 291, 1982

116. Thompson, R F The neurobtology of learning and memory. Scl-

ence 233 941-947, 1986 117. Thomson, A M Glycme modulation of the NMDA receptor/chan-

nel complex Trends Neuroscl. 12:349-353, 1989. 118 Tocco, G , Uenlshl. N , Thompson, J. K , Weiss, G , Baudry, M.,

Thompson, R F. Qulsqualate receptor binding in hlppocampus following classical condmonlng of the rabbit nictitating membrane Soc. Neuroscl Abstr 15 463, 1989.

119 Toffano, G., Aldmlo, C.; Balzano, M , Leon, A , Savolnl, G Regulation of GABA receptor binding to synaptic plasma membrane of rat cerebral cortex: the role of endogenous phosphohplds Brain Res 222.95-102, 1981

120 Vanderwolf, C. H Hlppocampal electrical actavlty and voluntary movement in the rat Electroencephalogr Chn Neurophyslol. 26 407--418, 1969

121 Welsz, D J.; Clark, T W ; Thompson, R. F. Increased activity of dentate granule cells dunng nictitating membrane response con- dltlonmg m rabbits. Behav Brain Res 12:145-154. 1984.

122 Wenzel, J , Matthles, H Morphological changes in the hlppocampal formation accompanying memory formation and long-term po- tentaatton In Welnberger, N , McGaugh, J L , Lynch, G , eds. Memory systems of the brain. New York: Guilford Press; 1985

123 Wilhams, J H ; Bliss, T. V Induction but not maintenance of calcium-induced long-term potentiation m dentate gyrus and area CA1 of the hlppocampal slice is blocked by nordlhydrogualaretlc acid Neurosci Lett 88(1)81-85, 1988

124 Wllhams, J H , Bhss, T V An in vitro study of the effect of hpoxygenase and cyclo-oxygenase lnhlbltors of arachldOnlC acid on the induction and maintenance of long-term potentmtlon m the h~p- pocampus Neuroscl Lett 107(1) 1-3. 1989

125 Zalutsky, R A., Nlcoll, R A Comparison of two forms of long- term potentiation in single hlppocampal neurons Science 248 1619-1624, 1990

126 Zwaal, R F., Bevers, E M , Comfunus, P , Roslng, J , Tdly, R H J , Verhallen, P F J Loss of membrane phosphohpld asymmetry dunng activation of blood platelets and slckled red cells, mechanisms and physiological significance. Mol Cell Biochem 91 23-31, 1989

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