A role for the cadherin family of cell adhesion molecules in hippocampal long-term potentiation

The cadherins are a family of cell-cell adhesion molecules that mediate Ca2+-dependent homophilic interactions between cells and transduce signals by interacting with cytoplasmic proteins. In the hippocampus, immunostaining combined with confocal microscopy revealed that both neural- (N-) and epithelial- (E-) cadherin are present at synaptic sites, implying a role in synaptic function. Pretreatment of hippocampal slices with antibodies (Abs) raised against the extracellular domain of either N-cad or E-cad had no effect on basal synaptic properties but significantly reduced long-term potentiation (LTP). Infusion of antagonistic peptides containing the His-Ala-Val (HAV) consensus sequence for cadherin dimerization also attenuated LTP induction without affecting previously established LTP. Because the intense synaptic stimulation associated with LTP induction might transiently deplete extracellular Ca2+ and hence potentially destabilize cadherin-cadherin interactions, we examined whether slices could be protected from inhibition by N-cad Abs or HAV peptides by raising the extracellular Ca2+ concentration. Indeed, we found that high extracellular Ca2+ prevented the block of LTP by these agents. Taken together, these results indicate that cadherins are involved in synaptic plasticity, and the stability of cadherin-cadherin bonds may be regulated by synaptic stimulation.     

Synaptic transmission and hippocampal long-term potentiation in olfactory cyclic nucleotide-gated channel type 1 null mouse

Field potential recording was used to investigate properties of synaptic transmission and long-term potentiation (LTP) at Schaffer collateral-CA1 synapses in both hippocampal slices of mutant mice in which the alpha-subunit of the olfactory cyclic nucleotide-gated channel (alpha3/OCNC)1 was rendered null and also in slices prepared from their wild-type (Wt) littermates. Several measures of basal synaptic transmission were unaltered in the OCNC1 knockout (KO), including maximum field excitatory postsynaptic potential (fEPSP) slope, maximum fEPSP and fiber volley amplitude, and the function relating fiber volley amplitude to fEPSP slope and paired-pulse facilitation. When a high-frequency stimulation protocol was used to induce LTP, similar responses were seen in both groups [KO: 1 min, 299 +/- 50% (mean +/- SE), 60 min, 123 +/- 10%; Wt: 1 min, 287 +/- 63%; 60 min, 132 +/- 19%). However, on theta-burst stimulation, the initial amplitude of LTP was smaller (1 min after induction, 147 +/- 16% of baseline) and the response decayed faster in the OCNC1 KO (60 min, 127 +/- 18%) than in Wt (1 min, 200 +/- 14%; 60 min, 169 +/- 19%). Analysis of waveforms evoked by LTP-inducing tetanic stimuli revealed a similar difference between groups. The development of potentiation throughout the tetanic stimulus was similar in OCNC1 KO and Wt mice when high-frequency stimulation was used, but OCNC1 KO mice showed a significant decrease when compared with Wt mice receiving theta-burst stimulation. These results suggest that activation of cyclic nucleotide-gated channels may contribute to the induction of LTP by weaker, more physiological stimuli, possibly via Ca2+ influx.     

Modified hippocampal long-term potentiation in PKC gamma-mutant mice

Calcium-phospholipid-dependent protein kinase (PKC) has long been suggested to play an important role in modulating synaptic efficacy. We have created a strain of mice that lacks the gamma subtype of PKC to evaluate the significance of this brain-specific PKC isozyme in synaptic plasticity. Mutant mice are viable, develop normally, and have synaptic transmission that is indistinguishable from wild-type mice. Long-term potentiation (LTP), however, is greatly diminished in mutant animals, while two other forms of synaptic plasticity, long-term depression and paired-pulse facilitation, are normal. Surprisingly, when tetanus to evoke LTP was preceded by a low frequency stimulation, mutant animals displayed apparently normal LTP. We propose that PKC gamma is not part of the molecular machinery that produces LTP but is a key regulatory component.     

Brain-derived neurotrophic factor alters the synaptic modification threshold in visual cortex

The effects of brain-derived neurotrophic factor (BDNF) were investigated on synaptic transmission and two forms of activity-dependent synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), in visual cortex slices prepared from young (P21 -28) rats. The slices treated for 2-5 h in BDNF showed no difference from control slices when a 'strong' tetanus was used (theta-burst stimulation) to elicit a maximal level of LTP but displayed significantly greater synaptic potentiation in response to a 'weak' (20 Hz) tetanus. The BDNF-treated slices also showed significantly less LTD in response to a 1 Hz tetanus. Thus, BDNF treatment alters the relationship between stimulation frequency and synaptic plasticity in the visual cortex, shifting the modification threshold to the left. The effects of BDNF on LTP and LTD induction may be attributed to the significant enhancement of synaptic responses that was observed during conditioning stimulation. These data suggest that one role of BDNF during development of the visual cortex may be to modulate the properties of synaptic plasticity, enhancing synaptic strengthening and reducing synaptic weakening processes which contribute to the formation of specific synaptic connections.     

Regulation of hippocampal synaptic plasticity by the tyrosine kinase receptor, REK7/EphA5, and its ligand, AL-1/Ephrin-A5

The Eph-related tyrosine kinase receptor, REK7/EphA5, mediates the effects of AL-1/Ephrin-A5 and related ligands and is involved in the guidance of retinal, cortical, and hippocampal axons during development. The continued expression of REK7/EphA5 in the adult brain, in particular in areas associated with a high degree of synaptic plasticity such as the hippocampus, raises the question of its function in the mature nervous system. In this report we examined the role of REK7/EphA5 in synaptic remodeling by asking if agents that either block or activate REK7/EphA5 affect synaptic strength in hippocampal slices from adult mouse brain. We show that a REK7/EphA5 antagonist, soluble REK7/EphA5-IgG, impairs the induction of long-term potentiation (LTP) without affecting other synaptic parameters such as normal synaptic transmission or paired-pulse facilitation. In contrast, perfusion with AL-1/Ephrin-A5-IgG, an activator of REK7/EphA5, induces a sustained increase in normal synaptic transmission that partially mimics LTP. The sustained elevation of normal synaptic transmission could be attributable to a long-lasting binding of the AL-1/Ephrin-A5-IgG to the endogenous REK7/EphA5 receptor, as revealed by immunohistochemistry. Furthermore, maximal electrical induction of LTP occludes the potentiating effects of subsequent treatment with AL-1/Ephrin-A5-IgG. Taken together these results implicate REK7/EphA5 in the regulation of synaptic plasticity in the mature hippocampus and suggest that REK7/EphA5 activation is recruited in the LTP induced by tetanization.     

The characteristics of the clinico-diagnostic and therapeutic treatment procedures for workers in the marine transport shore services who are ill with circulatory encephalopathy]

Heparin-binding growth-associated molecule (HB-GAM) is an 18-kDa developmentally regulated protein, which promotes neurite outgrowth, axonal guidance and synaptogenesis through interaction with cell-surface heparan-sulphate proteoglycans. We have studied the effect of HB-GAM on synaptic transmission and long-term potentiation (LTP) in the area CA1 of rat hippocampal slices, where HB-GAM mRNA is expressed in an activity-dependent manner. Injection of recombinant HB-GAM into the dendritic area inhibited tetanus-induced LTP without affecting baseline synaptic responses or the N-methyl-D-aspartate (NMDA)-receptor mediated transmission. HB-GAM did not depotentiate tetanus-induced LTP or prevent heterosynaptic LTP induced by application of tetraethylammonium (TEA), indicating that the effect was limited to early, synapse-specific stages of LTP induction. These results suggest that HB-GAM is involved in the regulation of synaptic plasticity in hippocampus.     

17β-estradiol modifies stress-induced and age-related changes in hippocampal synaptic plasticity.

The female steroid hormone 17β-estradiol enhances synaptic transmission and the magnitude of longterm potentiation (LTP) in adult rodent hippocampal slices. Long-term depression (LTD), another form of synaptic plasticity, occurs more prominently in hippocampal slices from aged rodents. A decrease in LTP has been recorded in hippocampal slices from adult rodents behaviorally stressed just before tissue preparation and electrophysiological recording. Here, the authors test the hypothesis that estrogen modifies synaptic plasticity in both adult and aged rodents, whether behaviorally stressed or not. Our results indicate that estrogen enhances LTP and attenuates LTD, thus producing a protective effect against both aging and stress. These results also provide new approaches that can be used to reverse age and stress-related learning and memory dysfunction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reversal of age-related alterations in synaptic plasticity by blockade of L-type Ca2+ channels

The role of L-type Ca2+ channels in the induction of synaptic plasticity in hippocampal slices of aged (22-24 months) and young adult (4-6 months) male Fischer 344 rats was investigated. Prolonged 1 Hz stimulation (900 pulses) of Schaffer collaterals, which normally depresses CA3/CA1 synaptic strength in aged rat slices, failed to induce long-term depression (LTD) during bath application of the L-channel antagonist nifedipine (10 microM). When 5 Hz stimulation (900 pulses) was used to modify synaptic strength, nifedipine facilitated synaptic enhancement in slices from aged, but not young, adult rats. This enhancement was pathway-specific, reversible, and impaired by the NMDA receptor (NMDAR) antagonist DL-2-amino-5-phosphonopentanoic acid (AP5). Induction of long-term potentiation (LTP) in aged rats, using 100 Hz stimulation, occluded subsequent synaptic enhancement by 5 Hz stimulation, suggesting that nifedipine-facilitated enhancement shares mechanisms in common with conventional LTP. Facilitation of synaptic enhancement by nifedipine likely was attributable to a reduction ( approximately 30%) in the Ca2+-dependent K+-mediated afterhyperpolarization (AHP), because the K+ channel blocker apamin (1 microM) similarly reduced the AHP and promoted synaptic enhancement by 5 Hz stimulation. In contrast, apamin did not block LTD induction using 1 Hz stimulation, suggesting that, in aged rats, the AHP does not influence LTD and LTP induction in a similar way. The results indicate that, during aging, L-channels can (1) facilitate LTD induction during low rates of synaptic activity and (2) impair LTP induction during higher levels of synaptic activation via an increase in the Ca2+-dependent AHP.     

Acute alcohol blocks neurosteroid modulation of synaptic transmission and long-term potentiation in the rat hippocampal slice

Effects of ethanol (22 mM) on the modulation of synaptic transmission and long-term potentiation (LTP) by the neurosteroid dehydroepiandrosterone sulfate (DHEAS; 10 microM) was examined in the in vitro rat hippocampal slice preparation. The synaptic responses were elicited by Schaffer collateral stimulation and recorded extracellularly in the somatic and dendritic regions of CA1 pyramidal neurons. LTP induction produced an increase (approximately 55% to 75%) in the amplitude of synaptic responses in ethanol and ethanol plus DHEAS (ethanol/DHEAS) treated slices. These increases were significantly smaller than the approximately 130% increase observed previously in slices treated with DHEAS, but were not significantly different from the approximately 82% increase observed in control slices. These results indicate that an ethanol/DHEAS interaction prevents the enhancement of LTP normally observed with DHEAS treatment of hippocampal slices. An ethanol/DHEAS interaction also altered DHEAS's effects on individual synaptic components of the synaptic response to Schaffer collateral stimulation. Ethanol applied before but not after DHEAS prevented DHEAS's enhancement of the NMDA receptor-mediated synaptic component. DHEAS's depression of the GABAA receptor-mediated synaptic component was also blocked by ethanol. Ethanol or DHEAS individually had no effect on the AMPA receptor-mediated synaptic component, but application of ethanol after DHEAS resulted in a small enhancement of this synaptic component, an effect that was not observed if ethanol was applied before DHEAS. These results show that ethanol and DHEAS interact, altering DHEAS's effects on synaptic transmission and LTP in the hippocampus. Such an interaction may be involved in ethanol's actions on the CNS and raises the possibility that ethanol and DHEAS may act via a common site or pathway.     

Ethanol effects on synaptic neurotransmission and tetanus-induced synaptic plasticity in hippocampal slices of chronic in vivo lead-exposed adult rats

The interaction of chronic in vivo lead exposure and acute in vitro ethanol treatment on synaptic neurotransmission and plasticity were studied using extracellular electrophysiological techniques in CA1 region of hippocampal brain slices from adult rats. Neither chronic lead exposure nor acute ethanol treatment had any significant effect on field excitatory postsynaptic potentials (EPSPs). In vivo lead exposure enhanced short-term potentiation (STP, potentiation that decays within 30 min) by 21% shortly after 'weak' tetanus, but had no effect on long-term potentiation (LTP, sustained at least 1 h). In vitro bath application of 60 mM ethanol inhibited STP by 35% and blocked LTP induced by 'weak' tetanus in slices from Pb exposed rats (500 ppm lead acetate, 56-70 days), while having no effect on STP or LTP in slices from control counterpart Na-exposed rats (pair-fed 216 ppm sodium acetate). In contrast, 'strong'-tetanus-induced LTP was abolished in Pb-exposed slices, and 60 mM ethanol slightly inhibited STP and blocked LTP in slices from Na-exposed rats. These differences could not be explained by differences in ethanol inhibition of NMDA-mediated field EPSPs because they were similarly reduced in slices from Na-exposed (30%) and Pb-exposed (25%) rats. These findings suggest that the strength of the tetanus used determines whether or not synaptic plasticity is blocked by either chronic lead exposure or acute ethanol treatment, and that even in adult rats, hippocampal synaptic LTP can be compromised by combined exposure to ethanol and lead. More importantly, these findings suggest the consequences of combined lead exposure and alcohol abuse in the adult human population may not be fully recognized yet.     

Heterogeneity in the distribution of actin filaments in the endothelial cells of arteries and arterioles in the rat kidney

The effect of two types of electrical stimulation designed to induce long-lasting plasticity of the Schaffer/commissural inputs to CA1 pyramidal neurons was investigated using in vitro hippocampal slices made from young (3-6 month) and old (24-27 month) Fischer 344 rats. The first stimulation paradigm, primed burst (PB) stimulation, consisted of a total of five physiologically patterned stimuli: a single priming pulse followed 170 ms later by a burst of four pulses at 200 Hz. The second stimulation paradigm, long-term potentiation (LTP) stimulation, consisted of a 200 Hz/1 second train (a total of 200 stimuli). Primed burst and LTP stimulation were equally effective at inducing a lasting increase in the population spike recorded from slices made from young rats. However, the enhancement of population spike amplitude produced by PB, but not LTP, stimulation was significantly less in slices made from old rats. These results suggest that the capacity of the hippocampus to demonstrate long-lasting synaptic plasticity is not altered with age, but that engaging plasticity-inducing mechanisms becomes more difficult. Furthermore, these data suggest that physiologically patterned paradigms for inducing long-lasting synaptic plasticity may more accurately assess the functional status of hippocampal memory encoding mechanisms than does conventional LTP stimulation.     

Picrotoxin-sensitive receptors mediate gamma-aminobutyric acid-induced modulation of synaptic plasticity in rat superior cervical ganglion

Activity-dependent changes of synaptic efficacy in the superior cervical ganglion (SCG) can be prevented by gamma-aminobutyric acid (GABA). We have studied the effects of picrotoxin (PTX) on GABA-mediated inhibition of long-term potentiation (LTP) of synaptic transmission in the rat SCG. Compound action potentials were recorded extracellularly in the postganglionic internal carotid nerve in response to preganglionic nerve stimulation. PTX (100 microM) antagonized the inhibition by exogenous GABA (250 microM) of LTP induced by strong tetanic stimulation (20 Hz, 20s, supramaximal stimulation, partial blockade of transmission by hexamethonium). Additionally, PTX alone (50 microM) facilitated the induction of LTP by a weak tetanus (20 Hz, 5 s, submaximal stimulation). These results further support previous data indicating that activation of GABAA-like receptors can prevent the occurrence of synaptic plasticity at this peripheral synapse.     

Postsynaptic complex spike bursting enables the induction of LTP by theta frequency synaptic stimulation

Long-term potentiation (LTP), a persistent enhancement of synaptic transmission that may be involved in some forms of learning and memory, is induced at excitatory synapses in the CA1 region of the hippocampus by coincident presynaptic and postsynaptic activity. Although action potentials back-propagating into dendrites of hippocampal pyramidal cells provide sufficient postsynaptic activity to induce LTP under some in vitro conditions, it is not known whether LTP can be induced by patterns of postsynaptic action potential firing that occur in these cells in vivo. Here we report that a characteristic in vivo pattern of action potential generation in CA1 pyramidal cells known as the complex spike burst enables the induction of LTP during theta frequency synaptic stimulation in the CA1 region of hippocampal slices maintained in vitro. Our results suggest that complex spike bursting may have an important role in synaptic processes involved in learning and memory formation, perhaps by producing a highly sensitive postsynaptic state during which even low frequencies of presynaptic activity can induce LTP.     

Effects of endothelin-1 on hippocampal synaptic plasticity

We examined the effects of puff application of endothelin (ET)-1 on the induction of long-term potentiation (LTP) and heterosynaptic long-term depression (LTD) in hippocampal CA1 slices. ET-1 applied 2 min prior to tetanus blocked the induction of LTP, but facilitated the induction of heterosynaptic LTD. These ET-1 effects on synaptic plasticity were dose-dependent, and not due to a generalized depression of baseline responses. ET-1 did not alter NMDA receptor-mediated responses. These data provide the first evidence that endothelin modulates activity-dependent synaptic plasticity, and the potency of these effects suggests that endogenous ET-1 may play an important role in regulating memory storage processes.     

Reg1ulatory role and molecular interactions of a cell-surface heparan sulfate proteoglycan (N-syndecan) in hippocampal long-term potentiation

The cellular mechanisms responsible for synaptic plasticity involve interactions between neurons and the extracellular matrix. Heparan sulfates (HSs) constitute a group of glycosaminoglycans that accumulate in the beta-amyloid deposits in Alzheimer's disease and influence the development of neuron-target contacts by interacting with other cell surface and matrix molecules. However, the contribution of HSs to brain function is unknown. We found that HSs play a crucial role in long-term potentiation (LTP), a finding that is consistent with the idea that converging molecular mechanisms are used in the development of neuron-target contacts and in activity-induced synaptic plasticity in adults. Enzymatic cleavage of HS by heparitinase as well as addition of soluble heparin-type carbohydrates prevented expression of LTP in response to 100 Hz/1 sec stimulation of Schaffer collaterals in rat hippocampal slices. A prominent carrier protein for the type of glycans implicated in LTP regulation in the adult hippocampus was identified as N-syndecan (syndecan-3), a transmembrane proteoglycan that was expressed at the processes of the CA1 pyramidal neurons in an activity-dependent manner. Addition of soluble N-syndecan into the CA1 dendritic area prevented tetanus-induced LTP. A major substrate of src-type kinases, cortactin (p80/85), and the tyrosine kinase fyn copurified with N-syndecan from hippocampus. Moreover, association of both cortactin and fyn to N-syndecan was rapidly increased after induction of LTP. N-syndecan may thus act as an important regulator in the activity-dependent modulation of neuronal connectivity by transmitting signals between extracellular heparin-binding factors and the fyn signaling pathway.     

Selective loss of hippocampal long-term potentiation, but not depression, following fluid percussion injury

We investigated the early effects of in vivo fluid percussion injury (FPI) on hippocampal synaptic potentials and excitability. In vitro field potential recordings and immunocytochemistry were performed in the CA1 region in slices from na?ve, post-FPI, or sham-operated rats. The following electrophysiological and morphological parameters were affected following FPI: (1) threshold for population spike generation was increased suggesting that post-FPI neurons were hypoexcitable; (2) long-term potentiation (LTP) could not be induced in injured hippocampi; (3) GFAP and inducible NO synthase (iNOS) immunoreactivity were enhanced post-FPI; and (4) following injury, synaptophysin immunoreactivity was enhanced in CA1 stratum radiatum. The effects of FPI on synaptic plasticity were LTP-specific, since long-term depression (LTD) could be equally induced and maintained in post-FPI, sham-operated and control slices. Sham-operated slices were characterized by synaptic excitability indistinguishable from na?ve controls, but displayed decreased ability for LTP production and expressed high levels of iNOS. We conclude that FPI causes a selective loss of LTP, possibly due to a previous potentiation induced by trauma as reflected by the increased expression of synaptic proteins. Sham surgical procedures were, however, not without effects on long-term potentiation itself; the latter effects appear to be mediated by an increased production of NO. Our study demonstrates for the first time that hippocampal slices can be used to investigate the correlates of in vivo FPI. Furthermore, we describe LTP-specific deficits in post-traumatic brain injury, suggesting that FPI can selectively erase one of the two main NMDA-dependent forms of synaptic plasticity in the hippocampus.     

Activation of p42 mitogen-activated protein kinase in hippocampal long term potentiation

Although classically studied as regulators of cell proliferation and differentiation, mitogen-activated protein kinases (MAPKs) are highly expressed in post-mitotic neurons of the adult nervous system. We have begun investigating the potential role of MAPKs in the regulation of synaptic plasticity in mature neurons. In particular, we have studied the regulation of two MAPK isoforms, p44 and p42 MAPK, in hippocampal long term potentiation (LTP), a system widely studied as a model for the cellular basis of learning and memory. We have found that p42 MAPK, but not p44 MAPK, is activated in area CA1 following direct stimulation of two required components of the LTP induction cascades: protein kinase C and the N-methyl--aspartate (NMDA) subtype of glutamate receptor. Furthermore, we have demonstrated that p42 MAPK, but not p44 MAPK, is activated in area CA1 in response to LTP-inducing high frequency stimulation and that this activation requires NMDA receptor stimulation. These data demonstrate that p42 MAPK can be regulated in an activity-dependent manner in the hippocampus and identify it as a potential component of the LTP induction cascades in area CA1. Such observations suggest that p42 MAPK might be an important regulator of synaptic plasticity in post-mitotic neurons.     

Unilateral labyrinthectomy downregulates glutamate receptor delta-2 expression in the rat vestibulocerebellum

Subcortical damage in neonates often has more severe consequences than in adults. Unilateral electrolytic hippocampal lesions in adult rats typically result in transient memory deficits, whereas neonatal lesions cause lasting memory impairments. We hypothesized that unilateral lesions made at birth may affect synaptic physiology in the contralateral hippocampus. Consequently, the ability to sustain long-term potentiation (LTP), a form of synaptic plasticity believed to underlie certain forms of memory, was compared between slices from the remaining hippocampus of rats lesioned as newborns and as adults. Initial studies showed that a train of 10 stimulation bursts patterned after the hippocampal theta rhythm produced robust and stable LTP both in slices from controls and rats lesioned at birth. However, a theta burst pattern of stimulation closer to intrinsic physiology (five burst pairs separated by 30 s each), induced significantly less LTP in slices from rats lesioned at birth compared to those from controls and rats lesioned as adults. To investigate possible mechanisms underlying the deficit, the degree of paired-pulse facilitation (PPF) as well as the amount of depolarization occurring between two successive theta bursts were analyzed. The lesion did not detectably change PPF characteristics, suggesting that presynaptic mechanisms are normal. However, the extent to which a burst response was increased by a prior burst was significantly diminished in slices from rats lesioned at birth compared to those from controls and rats lesioned as adults, indicating that postsynaptic factors involved in the initial triggering events of LTP are affected by the lesion. Reduced ability to sustain LTP in the remaining hippocampus may contribute to impaired memory function after unilateral neonatal hippocampal lesion.     

Alpha-subunit of calcium/calmodulin-dependent protein kinase II enhances gamma-aminobutyric acid and inhibitory synaptic responses of rat neurons in vitro

1. Here we report that in acutely isolated rat spinal dorsal horn neurons, the gamma-aminobutyric acid-A (GABAA) receptor can be regulated by calcium/calmodulin-dependent protein kinase II (CaM-KII). Intracellularly applied, the alpha-subunit of CaM-KII enhanced GABAA-receptor-activated current recorded with the use of the whole cell patch-clamp technique. This effect was associated with reduced desensitization of GABA responses. 2. GABA-induced currents are also potentiated by calyculin A, an inhibitor of protein phosphatases 1 and 2A. 3. Conventional intracellular recordings were made from hippocampal CA1 neurons in slices to determine the effect of intracellular application of CaM-KII on inhibitory synaptic potentials evoked by electrical stimulation of the stratum oriens/alveus. The inhibitory synaptic potential was enhanced by CaM-KII; this mechanism may contribute to long-term enhancement of inhibitory synaptic transmission and may also play a role in other forms of plasticity in the mammalian brain.     

Construction and overexpression in Escherichia coli of genetically engineered derivatives of penicillin-binding protein 2'' of Staphylococcus epidermidis

This paper reports a study of long-term potentiation (LTP) of perforant path synapses in CA1. Using rat hippocampal slices with CA3 and the dentate gyrus removed, stimulation of the perforant path evoked a population excitatory postsynaptic potential (pEPSP) that was negative-going in s. lacunosum-moleculare of CA1. High-frequency conditioning stimulation of the perforant pathway induced LTP of the perforant path pEPSP in slices disinhibited by the GABAA receptor antagonist bicuculline methiodide (20 microM). Conditioning of the perforant pathway in normal medium, however, failed to induce LTP. Potentiation of the perforant path pEPSP in the presence of bicuculline lasted at least 1 h, was specific to the tetanized pathway, and based on a threshold property, appeared associative in nature.