Priming stimulation modifies synaptic plasticity in the perforant path of hippocampal slice in rat

1 Introduction The ability to modify synaptic strength in an activity- dependent manner, either as long-term depression (LTD) or as long-term potentiation (LTP) is a fundamental feature of most central nervous system synapses. The properties of different forms of LTP in the rodent hippocampus have been exceedingly well studied. A less well studied but par- ticularly intriguing finding is that the capacity of many syn- apses for plastic changes itself is subject to modulation of subsequent …     

Modulatory metaplasticity induced by pregnenolone sulfate in the rat hippocampus: A leftward shift in LTP/LTD‐frequency curve

We recently have found that an acute application of the neurosteroid pregnenolone sulfate (PREGS) at 50 μM to rat hippocampal slices induces a long‐lasting potentiation (LLP_PREGS) via a sustained ERK2/CREB activation at perforant‐path/granule‐cell synapses in the dentate gyrus. This study is a follow up to investigate whether the expression of LLP_PREGS influences subsequent frequency‐dependent synaptic plasticity. Conditioning electric stimuli (CS) at 0.1–200 Hz were given to the perforant‐path of rat hippocampal slices expressing LLP_PREGS to induce long‐term potentiation (LTP) and long‐term depression (LTD). The largest LTP was induced at about 20 Hz‐CS, which is normally a subthreshold frequency, and the largest LTD at 0.5 Hz‐CS, resulting in a leftward‐shift of the LTP/LTD‐frequency curve. Furthermore, the level of LTP at 100 Hz‐CS was significantly attenuated to give band‐pass filter characteristics of LTP induction with a center frequency of about 20 Hz. The LTP induced by 20 Hz‐CS (termed 20 Hz‐LTP) was found to be postsynaptic origin and dependent on L‐type voltage‐gated calcium channel (L‐VGCC) but not on N‐methyl‐D ‐aspartate receptor (NMDAr). Moreover, the induction of 20 Hz‐LTP required a sustained activation of ERK2 that had been triggered by PREGS. In conclusion, the transient elevation of PREGS is suggested to induce a modulatory metaplasticity through a sustained activation of ERK2 in an L‐VGCC dependent manner. © 2009 Wiley‐Liss, Inc.     

Hippocampal long‐term potentiation that is elicited by perforant path stimulation or that occurs in conjunction with spatial learning is tightly controlled by beta‐adrenoreceptors and the locus coeruleus

The noradrenergic system, driven by locus coeruleus (LC) activation, plays a key role in the regulating and directing of changes in hippocampal synaptic efficacy. The LC releases noradrenaline in response to novel experience and LC activation leads to an enhancement of hippocampus‐based learning, and facilitates synaptic plasticity in the form of long‐term depression (LTD) and long‐term potentiation (LTP) that occur in association with spatial learning. The predominant receptor for mediating these effects is the β‐adrenoreceptor. Interestingly, the dependency of synaptic plasticity on this receptor is different in the hippocampal subfields whereby in the CA1 in vivo, LTP, but not LTD requires β‐adrenoreceptor activation, whereas in the mossy fiber synapse LTP and LTD do not depend on this receptor. By contrast, synaptic plasticity that is facilitated by spatial learning is highly dependent on β‐adrenoreceptor activation in both hippocampal subfields. Here, we explored whether LTP induced by perforant‐path (pp) stimulation in vivo or that is facilitated by spatial learning depends on β‐adrenoreceptors. We found that under both LTP conditions, antagonising the receptors disabled the persistence of LTP. β‐adrenoreceptor‐antagonism also prevented spatial learning. Strikingly, activation of the LC before high‐frequency stimulation (HFS) of the pp prevented short‐term potentiation but not LTP, and LC stimulation after pp‐HFS‐induced depotentiation of LTP. This depotentiation was prevented by β‐adrenoreceptor‐antagonism. These data suggest that β‐adrenoreceptor‐activation, resulting from noradrenaline release from the LC during enhanced arousal and learning, comprises a mechanism whereby the duration and degree of LTP is regulated and fine tuned. This may serve to optimize the creation of a spatial memory engram by means of LTP and LTD. This process can be expected to support the special role of the dentate gyrus as a crucial subregional locus for detecting and processing novelty within the hippocampus. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.     

Diabetes mellitus concomitantly facilitates the induction of long-term depression and inhibits that of long-term potentiation in hippocampus

Memory impairments, which occur regularly across species as a result of ageing, disease (such as diabetes mellitus) and psychological insults, constitute a useful area for investigating the neurobiological basis of learning and memory. Previous studies in rats found that induction of diabetes (with streptozotocin, STZ) impairs long‐term potentiation (LTP) but enhances long‐term depression (LTD) induced by high‐ (HFS) and low‐frequency stimulations (LFS), respectively. Using a pairing protocol under whole‐cell recording conditions to induce synaptic plasticity at Schaffer collateral synapses in hippocampal CA1 slices, we show that LTD and LTP have similar magnitudes in diabetic and age‐matched control rats. But, in diabetic animals, LTD is induced at more polarized and LTP more depolarized membrane potentials (V_ms) compared with controls: diabetes produces a 10 mV leftward shift in the threshold for LTD induction and 10 mV rightward shift in the LTD–LTP crossover point of the voltage–response curve for synaptic plasticity. Prior repeated short‐term potentiations or LTP are known to similarly, though reversibly, lower the threshold for LTD induction and raise that for LTP induction. Thus, diabetes‐ and activity‐dependent modulation of synaptic plasticity (referred to as metaplasticity) display similar phenomenologies. In addition, compared with naïve synapses, prior induction of LTP produces a 10 mV leftward shift in V_ms for inducing subsequent LTD in control but not in diabetic rats. This could indicate that diabetes acts on synaptic plasticity through mechanisms involved in metaplasticity. Persistent facilitation of LTD and inhibition of LTP may contribute to learning and memory impairments associated with diabetes mellitus.     

Group I metabotropic glutamate receptors regulate the frequency-response function of hippocampal CA1 synapses for the induction of LTP and LTD

Synaptically released glutamate binds to ionotropic or metabotropic glutamate receptors. Metabotropic glutamate receptors (mGluRs) are G‐protein‐coupled receptors and can be divided into three subclasses (Group I–III) depending on their pharmacology and coupling to signal transduction cascades. Group I mGluRs are coupled to phospholipase C and are implicated in several important physiological processes, including activity‐dependent synaptic plasticity, but their exact role in synaptic plasticity remains unclear. Synaptic plasticity can manifest itself as an increase or decrease of synaptic efficacy, referred to as long‐term potentiation (LTP) and long‐term depression (LTD). The likelihood, degree and direction of the change in synaptic efficacy depends on the history of the synapse and is referred to as ‘metaplasticity’. We provide direct experimental evidence for an involvement of group I mGluRs in metaplasticity in CA1 hippocampal synapses. Bath application of a low concentration of the specific group I agonist 3,5‐dihydroxyphenylglycine (DHPG), which does not affect basal synaptic transmission, resulted in a leftward shift of the frequency–response function for the induction of LTD and LTP in naïve synapses. DHPG resulted in the induction of LTP at frequencies which induced LTD in control slices. These alterations in the induction of LTD and LTP resemble the metaplastic changes observed in previously depressed synapses. In addition, in the presence of DHPG additional potentiation could be induced after LTP had apparently been saturated. These findings provide strong evidence for an involvement of group I mGluRs in the regulation of metaplasticity in the CA1 field of the hippocampus.     

Metaplasticity: new insights through electrophysiological investigations

The term synaptic plasticity describes the ability of excitatory synapses to undergo activity-driven long-lasting changes in the efficacy of basal synaptic transmission. This change may be expressed as a long-term potentiation (LTP) or as a long-term depression (LTD). Metaplasticity is a higher-order form of synaptic plasticity that regulates the expression of both LTP and LTD through processes that are initiated by cellular activity that precedes a later bout of plasticity-inducing synaptic activity. Activation by prior synaptic activity and later expression as a facilitation or inhibition of activity-dependent synaptic plasticity are fundamental properties of metaplasticity. The intracellular mechanisms which support metaplasticity appear to be closely linked to those of synaptic plasticity, hence there are significant technical challenges to overcome in order to elucidate those mechanisms specific to metaplasticity. This review will examine the progress in the characterization of metaplasticity over the last decade or so with a focus on findings gained using electrophysiological techniques. It will look at the techniques applied, the brain regions investigated and the knowledge gained from the application of a wide range of protocols designed to examine the influence of varied forms of prior synaptic activity on later, activity-induced, synaptic plasticity.     

Prenatal morphine exposure enhances seizure susceptibility but suppresses long-term potentiation in the limbic system of adult male rats

The present study examined the effects of prenatal morphine exposure on NMDA-dependent seizure susceptibility in the entorhinal cortex (EC), and on activity-dependent synaptic plasticity at Schaffer collateral and perforant path synapses in the hippocampus. During perfusion with Mg(2+)-free ACSF, an enhancement of epileptiform discharges was found in the EC of slices from prenatally morphine-exposed male rats. A submaximal tetanic stimulation (2x50 Hz/1 s) in control slices elicited LTP at the Schaffer collateral-CA1 synapses, but neither LTP nor LTD was evoked at the perforant path-DG synapses. In slices from prenatally morphine-exposed adult male rats, long-term potentiation of synaptic transmission was not observed at Schaffer collateral-CA1 synapses, while the submaximal tetanus now elicited frank LTD of synaptic EPSPs at perforant path synapses. These data suggest that prenatal morphine exposure enhances the susceptibility of entorhinal cortex to the induction of epileptiform activity, but shifts long-term plasticity of hippocampal synapses in favor of LTD.     

Long-term synaptic morphometry changes after induction of long-term potentiation and long-term depression in the dentate gyrus of awake rats are not simply mirror phenomena

Mechanisms of expression of long-term synaptic plasticity are believed to involve morphological changes of the activated synapses and remodelling of connectivity. Here, we investigated changes in synaptic and neuronal parameters in the dentate gyrus 24 h after induction of long-term potentiation (LTP) and long-term depression (LTD) in awake rats. In dentate granule cells, tetanization of the medial or lateral perforant paths induces LTP in specific synaptic bands along the dendrites in the middle and outer molecular layers, respectively, and tetanization of the lateral path induces robust LTD heterosynaptically in the middle molecular layer. This functional segregation allowed us to assess morphological changes associated with LTP and LTD in each pathway in the same population of neurons. Electron microscopy and unbiased counting methods were used to estimate neuronal density, axospinous, axodendritic and perforated synapse density, multiple synapse bouton density and postsynaptic density (PSD) area. Whereas there was no change in neuronal density, PSD area and multiple synapse boutons 24 h after either LTP or LTD, there was a noninput-specific increase in unperforated axospinous synapses after both LTP and LTD. However, we found that LTP of the medial, but not lateral, perforant path is associated with a specific increase in perforated axospinous synapses in the potentiated area. We also show that heterosynaptic LTD is associated with an input-specific increase in axodendritic synapse density. These results suggest that each perforant pathway may differ with respect to the nature of LTP-induced long-term changes and show that morphologically LTD is not simply the converse of LTP.     

Associative long-term potentiation (LTP) among extrinsic afferents of the hippocampal CA3 region in vivo

Monosynaptic perforant path projections to the CA3 region of the hippocampus are anatomically and physiologically substantial pathways that relay cortical input directly to the hippocampus proper. Despite the suggested relevance of these direct pathways in models of information processing within the CA3 region, surprisingly few studies have characterized synaptic plasticity in these direct cortical projections to the CA3 region. We assessed the ability of perforant path projections, and commissural/associational projections to the hippocampal CA3 region to both induce or display associative LTP in vivo. In pentobarbital-anesthetized adult rats, trains delivered to either the medial or lateral perforant pathway at current intensities normally insufficient to induce LTP displayed associative LTP when these same trains were delivered in conjunction with high-intensity trains to the alternate perforant pathway. Similarly, associative LTP is induced at intrinsic commissural/associational–CA3 (C/A–CA3) synapses when weak C/A trains were delivered in conjunction with high-intensity trains to either the medial or lateral perforant pathway. Associative LTP also was observed at medial and lateral perforant path–CA3 synapses when weak perforant path trains were tetanized in conjunction with high-intensity trains delivered to C/A–CA3 synapses. Thus direct perforant path–CA3 synapses and commissural/associational–CA3 synapses can modify and be modified by other CA3 afferents in an associative manner, verifying a requirement for synaptic plasticity explicit in models of autoassociative information processing in the CA3 region.     

Hippocampal synaptic metaplasticity requires the activation of NR2B-containing NMDA receptors

The potential to exhibit synaptic plasticity itself is modulated by previous synaptic activity, which has been termed as metaplasticity. In this paper, we demonstrated that the activation of N-methyl-d-aspartate (NMDA) receptor 2B (NR2B) subunit in NNDA receptors was required for hippocampal metaplasticity at Schaffer collateral-commissural fiber-CA1 synapses. Brief 5 Hz priming stimulation did not cause long-term synaptic plasticity; however, it could result in the inhibition of subsequently evoked long-term potentiation (LTP). Meanwhile, the application of selective antagonists for NR2B subunit of NMDA receptors after delivering priming stimulation could block the metaplasticity. In contrast, LTP induction was not affected by NR2B antagonists in slices without pre-treatment of priming stimulation. These results indicated that the activation of NR2B-containing NMDA receptors was required for metaplasticity.     

Forebrain NR2B overexpression enhancing fear acquisition and long‐term potentiation in the lateral amygdala

N‐methyl‐d ‐aspartic acid (NMDA) receptor‐dependent long‐term potentiation (LTP) at the thalamus–lateral amygdala (T‐LA) synapses is the basis for acquisition of auditory fear memory. However, the role of the NMDA receptor NR2B subunit in synaptic plasticity at T‐LA synapses remains speculative. In the present study, using transgenic mice with forebrain‐specific overexpression of the NR2B subunit, we have observed that forebrain NR2B overexpression results in enhanced LTP but does not alter long‐term depression (LTD) at the T‐LA synapses in transgenic mice. To elucidate the cellular mechanisms underlying enhanced LTP at T‐LA synapses in these transgenic mice, AMPA and NMDA receptor‐mediated postsynaptic currents have been measured. The data show a marked increasing in the amplitude and decay time of NMDA receptor‐mediated currents in these transgenic mice. Consistent with enhanced LTP at T‐LA synapses, NR2B‐transgenic mice exhibit better performance in the acquisition of auditory fear memory than wild‐type littermates. Our results demonstrate that up‐regulation of NR2B expression facilitates acquisition of auditory cued fear memory and enhances LTP at T‐LA synapses.     

Hippocampal long-term depression is enhanced, depotentiation is inhibited and long-term potentiation is unaffected by the application of a selective c-Jun N-terminal kinase inhibitor to freely behaving rats

Synaptic plasticity is regarded as the major candidate mechanism for synaptic information storage and memory formation in the hippocampus. Mitogen‐activated protein kinases have recently emerged as an important regulatory factor in many forms of synaptic plasticity and memory. As one of the subfamilies of mitogen‐activated protein kinases, extracellular‐regulated kinase is involved in the in vitro induction of long‐term potentiation (LTP), whereas p38 mediates metabotropic glutamate receptor‐dependent long‐term depression (LTD) in vitro. Although c‐Jun N‐terminal kinase (JNK) has also been implicated in synaptic plasticity, the in vivo relevance of JNK activity to different forms of synaptic plasticity remains to be further explored. We investigated the effect of inhibition of JNK on different forms of synaptic plasticity in the dentate gyrus of freely behaving adult rats. Intracereboventricular application of c‐Jun N‐terminal protein kinase‐inhibiting peptide (D‐JNKI) (96 ng), a highly selective JNK inhibitor peptide, did not affect basal synaptic transmission but reduced neuronal excitability with a higher dose (192 ng). Application of D‐JNKI, at a concentration that did not affect basal synaptic transmission, resulted in reduced specific phosphorylation of the JNK substrates postsynaptic density 95kD protein (PSD 95) and c‐Jun, a significant enhancement of LTD and a facilitation of short‐term depression into LTD. Both LTP and short‐term potentiation were unaffected. An inhibition of depotentiation (recovery of LTP) occurred. These data suggest that suppression of JNK‐dependent signalling may serve to enhance synaptic depression, and indirectly promote LTP through impairment of depotentiation.     

Fimbrial control of bidirectional synaptic plasticity of medial perforant path-dentate transmission

Lesions of the fimbria-fornix (FF) tract cause profound impairments of cognitive ability in animals. Our previous study showed that spatial performance correlates with long-term potentiation (LTP) of the dentate gyrus (DG), but not of the CA1 region, in rats with bilateral FF lesions, suggesting that FF lesions selectively inhibited LTP in the DG. The cortical input to the DG is anatomically and physiologically divided into two types of afferents, i.e., the medial perforant path (MPP) and the lateral perforant path (LPP), which show distinct synaptic properties. To elucidate the difference in the FF modulation of these two inputs, field responses were recorded from MPP- or LPP-DG synapses in anesthetized rats. MPP-DG synapses of rats with FF lesions displayed neither LTP in response to theta-burst stimulation nor long-term depression (LTD) in response to low-frequency burst stimulation. In contrast to the MPP, LPP-DG synapses showed normal LTP in rats with FF lesions. The low-frequency burst stimulation could not induce LTD at LPP-DG synapses in either intact or FF-lesioned rats. These results suggest that the FF pathway selectively supports the mechanisms of bidirectional synaptic plasticity at MPP-DG synapses. This study provides new insights into external control of information processing in the hippocampus.     

Heterosynaptic long‐term depression mediated by ATP released from astrocytes

Heterosynaptic long‐term depression (hLTD) at untetanized synapses accompanying the induction of long‐term potentiation (LTP) spatially sharpens the activity‐induced synaptic potentiation; however, the underlying mechanism remains unclear. We found that hLTD in the hippocampal CA1 region is caused by stimulation‐induced ATP release from astrocytes that suppresses transmitter release from untetanized synaptic terminals via activation of P2Y receptors. Selective stimulation of astrocytes expressing channelrhodopsin‐2, a light‐gated cation channel permeable to Ca²⁺, resulted in LTD of synapses on neighboring neurons. This synaptic modification required Ca²⁺ elevation in astrocytes and activation of P2Y receptors, but not N‐methyl‐D ‐aspartate receptors. Furthermore, blocking P2Y receptors or buffering astrocyte intracellular Ca²⁺ at a low level prevented hLTD without affecting LTP induced by SC stimulation. Thus, astrocyte activation is both necessary and sufficient for mediating hLTD accompanying LTP induction, strongly supporting the notion that astrocytes actively participate in activity‐dependent synaptic plasticity of neural circuits. © 2012 Wiley Periodicals, Inc.     

Activation of the medial septal area attenuates LTP of the lateral perforant path and enhances heterosynaptic LTD of the medial perforant path in aged rats

Age-related memory impairments may be due to dysfunction of the septohippocampal system. The medial septal area (MSA) provides the major cholinergic projection to the hippocampus and is critical for memory. Knowledge of the neurobiological mechanisms by which the cholinergic system can attenuate age-related memory loss can facilitate the development of effective cognitive enhancers. At present, one of the best neurobiological models of memory formation is long-term potentiation/long-term depression (LTP/LTD). In previous studies, intraseptal infusion of the muscarinic agonist oxotremorine, which excites MSA neurons, improved memory in aged rats. The present study examined LTP and LTD in aged Fisher 344 rats following intraseptal infusion of oxotremorine. LTP and LTD were assessed using the slope of the EPSP recorded from the hilar region of the dentate gyrus. Induction of LTP was blocked in the lateral perforant path, but not in the medial perforant path, following intraseptal infusions of oxotremorine. The generation and amplitude of heterosynaptic LTD was enhanced in the medial perforant path, but not in the lateral perforant path. The results provide evidence that pharmacological activation of the MSA can modulate LTP and LTD in the hippocampus of aged rats. The implications of these results with respect to memory and synaptic plasticity in the hippocampus are discussed.     

Increase in syntaxin 1B and glutamate release in mossy fibre terminals following induction of LTP in the dentate gyrus: a candidate molecular mechanism underlying transsynaptic plasticity

A growing body of evidence suggests that modulation of certain proteins of the exocytotic machinery is, in part, involved in the biochemical changes that underlie long-term synaptic plasticity. We have previously shown that the induction of long-term potentiation (LTP) at perforant path to dentate granule cell synapses in the rat hippocampus induces changes in the mRNA levels of syntaxin 1B and synapsin I, known to be involved in neurotransmitter release. Immunohistochemical staining suggested that concomitant changes in these proteins occurred at mossy fibre synapses, downstream of those synapses at which LTP was induced, leading us to postulate that such a mechanism might underlie a form of transsynaptic plasticity. Here we have used a specific mossy-fibre synaptosome preparation to quantify levels of proteins and measure, using a chemiluminescent glutamate assay, depolarization-induced glutamate release from these synaptosomes after induction of LTP in the dentate gyrus in vivo. We show that 5 h after the induction of LTP, there is an increase in the protein levels of syntaxin 1B and, although to a lesser extent, the synapsins I and II, associated with an increase in depolarization-induced release of glutamate within these terminals. Increases in both the protein levels and glutamate release were not observed when dentate gyrus LTP was blocked by an NMDA receptor antagonist. From these results we propose a molecular mechanism for the propagation of synaptic plasticity through hippocampal circuits.     

Long‐term depression of inhibitory synaptic transmission induced by spike‐timing dependent plasticity requires coactivation of endocannabinoid and muscarinic receptors

The precise timing of pre‐postsynaptic activity is vital for the induction of long‐term potentiation (LTP) or depression (LTD) at many central synapses. We show in synapses of rat CA1 pyramidal neurons in vitro that spike timing dependent plasticity (STDP) protocols that induce LTP at glutamatergic synapses can evoke LTD of inhibitory postsynaptic currents or STDP‐iLTD. The STDP‐iLTD requires a postsynaptic Ca²⁺ increase, a release of endocannabinoids (eCBs), the activation of type‐1 endocananabinoid receptors and presynaptic muscarinic receptors that mediate a decreased probability of GABA release. In contrast, the STDP‐iLTD is independent of the activation of nicotinic receptors, GABA_BRs and G protein‐coupled postsynaptic receptors at pyramidal neurons. We determine that the downregulation of presynaptic Cyclic adenosine monophosphate/protein Kinase A pathways is essential for the induction of STDP‐iLTD. These results suggest a novel mechanism by which the activation of cholinergic neurons and retrograde signaling by eCBs can modulate the efficacy of GABAergic synaptic transmission in ways that may contribute to information processing and storage in the hippocampus. © 2013 Wiley Periodicals, Inc.     

The effects of intra‐hippocampal L‐thyroxine infusion on long‐term potentiation and long‐term depression: A possible role for the αvβ3 integrin receptor

Although the effects of long‐term experimental dysthyroidism on long‐term potentiation (LTP) and long‐term depression (LTD) have been documented, the relationship between LTP/LTD and acute administration of L‐thyroxine (T4) has not been described. Here, we investigated the effects of intra‐hippocampal administration of T4 on synaptic plasticity in the dentate gyrus of the hippocampal formation. After a 15‐minute baseline recording, LTP and LTD were induced by application of high‐ and low‐frequency stimulation protocols, respectively. Infusions of saline or T4 and tetraiodothyroacetic acid (tetrac), a T4 analog that inhibits binding of iodothyronines to the integrin αvβ3 receptor, either alone or together, were made during the stimulation protocols. The averages of the excitatory postsynaptic potential (EPSP) slopes and population spike (PS) amplitudes, between 55 to 60 minutes, were used as a measure of the LTP/LTD magnitude and were analyzed by two‐way univariate ANOVA with T4 and tetrac as between‐subjects factors. The input–output curves of the infusion groups were comparable to each other, as shown by the non significant interaction observed between stimulus intensity and infused drug. The magnitude of the LTP in T4‐infused rats was significantly lower as compared to saline‐infused rats. Both the PS amplitude and the EPSP slope were depressed more markedly with T4 infusion than with saline, tetrac, and T4 + tetrac infusion. Data of this study provide in vivo evidence that T4 can promote LTD over LTP via the integrin αvβ3 receptor, and that the effect of endogenous T4 on this receptor can be suppressed by tetrac in the hippocampus. © 2016 Wiley Periodicals, Inc.     

NMDA-dependent heterosynaptic long-term depression in the dentate gyrus of anaesthetized rats.

This report examines the inductive mechanisms involved in long-term heterosynaptic depression (LTD) in the dentate gyrus of anaesthetized rats. Associative and non-associative stimulus protocols were implemented, using the ipsilateral medial and lateral perforant path inputs to the dentate gyrus as the test pathways. In all experiments, the medial perforant path (MPP) received the conditioning stimuli which consisted of eight stimulus trains of 2 s duration, spaced 1 minute apart. Within each train the stimuli occurred as a burst of 5 pulses at 100 Hz, repeated at 200 ms intervals. The lateral perforant path (LPP) served as the test pathway in all of the initial experiments. In the associative condition, it received single pulses equally spaced between the medial path bursts. In the non-associative condition, no lateral path stimuli were given during the medial path trains. In both conditions, the application of the conditioning stimuli resulted in a long-term potentiation (LTP) of the medial path evoked responses (P less than 0.001), while the lateral path responses showed LTD (P less than 0.001). A two-way analyses of variance revealed there to be no difference between the two paradigms in the expression of LTP or LTD in naive pathways or in their ability to depress a potentiated pathway (P greater than 0.05) An occlusion test also showed there to be no further decreases in synaptic efficacy with the associative paradigm after the lateral path synapses were saturated with non-associative LTD.(ABSTRACT TRUNCATED AT 250 WORDS)