Recruitment of new sites of synaptic transmission during the cAMP-dependent late phase of LTP at CA3-CA1 synapses in the hippocampus

Long-term potentiation at CA3-CA1 hippocampal synapses exhibits an early phase and a late phase, which can be distinguished by their underlying molecular mechanisms. Unlike the early phase, the late phase is dependent on both cAMP and protein synthesis. Quantal analysis of unitary synaptic transmission between a single presynaptic CA3 neuron and a single postsynaptic CA1 neuron suggests that, under certain conditions, the early phase of LTP involves an increase in the probability of release of a single quantum of transmitter from a single presynaptic release site, with no change in the number of quanta that are released or in postsynaptic sensitivity to transmitter. Here, we show that the cAMP-induced late phase of LTP involves an increase in the number of quanta released in response to a single presynaptic action potential, possibly due to an increase in the number of sites of synaptic transmission between a single CA3 and a single CA1 neuron.     

Evidence for postsynaptic induction and expression of NMDA receptor independent LTP

Whole cell/patch-clamp and extracellular field potential recordings were used to study the induction and expression of N-methyl-D-aspartate (NMDA) receptor independent long-term potentiation (LTP) in area CA1 of the in vitro rat hippocampus. Induction of NMDA receptor independent LTP was prevented by manipulations that inhibited postsynaptic depolarization during tetanic stimulation: direct hyperpolarization of postsynaptic neurons and bath application of an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptor antagonist. NMDA receptor independent LTP also was blocked by intracellular application of the lidocaine derivative, N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium bromide (QX-314), to CA1 pyramidal neurons. These results complement the previous findings that NMDA receptor independent LTP was inhibited by postsynaptic injections of the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid and also was inhibited by a L-type voltage-dependent calcium channel antagonist (nifedipine). Collectively, these data make a strong case for the postsynaptic induction of this form of LTP. This paper also provides evidence for postsynaptic expression of NMDA receptor independent LTP. In an experiment where AMPA- and NMDA-receptor-mediated excitatory postsynaptic potentials (EPSPs) were isolated pharmacologically, LTP was found for only the AMPA-receptor-mediated EPSPs. In a separate experiment, paired-pulse facilitation (PPF) was measured during NMDA receptor independent LTP. Although there was an initial decrease in PPF, suggesting a posttetanic increase in the probability of glutamate release, the change in PPF decayed within 30-40 min of the tetanic stimulation, whereas the magnitude of the LTP was constant over this same time period. In addition, the LTP, but not the corresponding change in PPF, was blocked by the metabotropic glutamate receptor antagonist (+/-)-alpha-methyl-4-carboxyphenylglycine. These results are accounted for most easily by a selective increase in postsynaptic AMPA receptor function, but one type of presynaptic modification-an increase in the number of release sites without an overall change in the probability of release-also could account for these results (assuming that the level of glutamate release before LTP induction fully saturated NMDA, but not AMPA, receptors). One possible presynaptic modification, an increase in axon excitability, was ruled out by analysis of the presynaptic fiber volley, which was not increased at any time after LTP induction.     

Hippocampal long-term potentiation preserves the fidelity of postsynaptic responses to presynaptic bursts

Hippocampal cells often fire prolonged bursts of action potentials, resulting in dynamic modulation of postsynaptic responses; yet long-term potentiation (LTP) has routinely been studied using only single presynaptic stimuli given at low frequency. Recent work on neocortical synapses has suggested that LTP may cause a "redistribution of synaptic strength" in which synaptic responses to the first stimulus of a presynaptic burst of action potentials are potentiated with later responses depressed. We have examined whether this redistribution occurs at hippocampal synapses during LTP. Using prolonged bursts that result in maximal short-term depression of later responses within the burst, we found that LTP resulted in a uniform potentiation of individual responses throughout the burst rather than a redistribution of synaptic strength. This occurred both at Schaffer collateral-CA1 synapses and at CA3-CA3 synapses, the latter being activated and monitored using paired recordings. Thus in the hippocampus, LTP preserves the fidelity of postsynaptic responses to presynaptic bursts by a uniform increase rather than a redistribution of synaptic strength, a finding that suggests there are important differences between neocortex and hippocampus in how long-term changes in synaptic strength are used to encode new information.     

Importance of polysynaptic inputs and horizontal connectivity in the generation of tetanus-induced long-term potentiation in the rat auditory cortex

Supragranular pyramidal neurons in the adult rat auditory cortex (AC) show marked long-term potentiation (LTP) of population spikes after tetanic white matter stimulation (TS). For determination of whether this marked LTP is specific to AC, LTP in rat AC slices was compared with LTP in slices of the visual cortex (VC). The amplitude of TS-induced LTP in AC was twice that in VC. LTP of EPSPs was also studied with perforated patch or whole-cell recording. Although the amplitude of TS-induced LTP of EPSPs in AC was larger that in VC, no cortical difference was found in LTP elicited by low-frequency stimulation paired with current injection. Neocortical LTP is dependent on the activation of NMDA receptors, and induction of LTP requires postsynaptic depolarization for removal of Mg2+ blockade of NMDA receptors. The postsynaptic depolarization elicited by TS in supragranular pyramidal neurons in AC was significantly larger than that in VC. Cutting of supragranular horizontal connections resulted in a decrease in the depolarization amplitude in AC but an increase in the depolarization amplitude in VC. The cortical difference in TS-induced LTP was diminished in the slices in which horizontal connections in supragranular layers were cut. The estimated density of horizontal axon collaterals of supragranular pyramidal neurons in AC was approximately twice that in VC. These results strongly suggest that the marked polysynaptic and postsynaptic depolarization during TS and the resulting marked LTP in AC are attributed to well developed horizontal axon collaterals of supragranular pyramidal neurons in AC.     

Effects of aniracetam after LTP induction are suggestive of interactions on the kinetics of the AMPA receptor channel

The modulatory influence of aniracetam, a drug which reversibly modifies the kinetic properties of AMPA-type glutamate receptors, on synaptic responses is reported to be detectably changed by the induction of long-term potentiation (LTP). The present study used hippocampal slices to examine three issues arising from this result. First, possible contributions of inhibitory currents and postsynaptic spiking to the aniracetam/LTP interaction were investigated with infusions of GABA receptor antagonists and topical applications of tetrodotoxin. Second, tests were carried out to determine if the altered response to aniracetam is sufficiently persistent to be a plausible substrate for the extremely stable LTP effect. Third, the nature of the change responsible for the aniracetam/LTP interaction was explored with waveform analyses and a kinetic model of the AMPA receptor. The following results were obtained. LTP reduced the effect of aniracetam on the amplitude but increased its effect on the decay time constant of field EPSPs recorded under conditions in which local spiking and inhibitory responses were blocked. The LTP-induced change in the effect of aniracetam was extremely stable in that it was still evident 75 min after induction of potentiation. Finally, the waveform distortions introduced by LTP and aniracetam could be corrected by uniform stretching of the responses, suggesting that the changes introduced by each of the manipulations are unitary in nature. These distortions and the interactions between them could be reproduced in the AMPA receptor model by representing LTP as an acceleration of channel gating kinetics.     

Block of HFS-induced LTP in the dentate gyrus by 1S,3S-ACPD: further evidence against LTP as a model for learning

We have previously shown that block of high-frequency stimulation (HFS) induced long-term potentiation (LTP) of synaptic transmission in area CA1 by (1S,3S)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3S-ACPD; 5 microliters of a 20 mM solution), an agonist at group II metabotropic glutamate receptors, did not prevent animals from learning a spatial task. Here we show that the same dose of 1S,3S-ACPD also blocked the induction of HFS-induced LTP of the slope of the excitatory postsynaptic potential and of the amplitude of the population spike in the dentate gyrus. We conclude that HFS-induced LTP in the dentate gyrus is not a good model for memory formation.     

Role of temporal summation in age-related long-term potentiation-induction deficits

Hippocampal long-term potentiation (LTP) is reduced in aged relative to young F-344 rats when peri-threshold stimulation protocols (several stimulus pulses at 100-200 Hz) are used. The present study was designed to examine the possibility that this LTP-induction deficit is caused by a reduced overlap of Schaffer-collateral inputs onto CA1 pyramidal cells (input cooperativity). This reduced input cooperativity would decrease the levels of postsynaptic depolarization during LTP induction, which might account for the age-related LTP deficit. Both behavioral data (Morris Water Maze) and electrophysiological data (intracellular recordings from hippocampal slices) were collected from adult and aged F-344 rats. To counter the effects of reduced input cooperativity, stimulus intensities were adjusted to elicit baseline excitatory postsynaptic potentials (EPSPs) of equivalent amplitude in aged and young rats. Contrary to expectations, however, an age-related LTP-induction deficit was still observed. Further evaluation of the electrophysiological data revealed that temporal summation of multiple EPSPs during high-frequency stimulation was impaired in the aged rats. Thus, despite the equalization across age groups of the baseline EPSP amplitudes, the cells of aged rats were less depolarized during the LTP-inducing stimulation than were those of young rats. This reduced total depolarization was not an artifact of the higher stimulus intensity used on aged animals, nor was it caused by a failure of aged rats' CA1 afferents to follow high-frequency stimulation. The present data therefore suggest that there is a deficit in the ability of aged rats' synapses to provide the sustained depolarization necessary to active the LTP-induction cascade.     

Long-term potentiation in hippocampal slices induced by temporary suppression of glycolysis

1. Temporary suppression of glycolysis by 2-deoxy-D-glucose (2-DG)-long enough to abolish CA1 population spikes (PSs) and reduce field excitatory postsynaptic potentials (EPSPs) by two-thirds-is followed by a sustained rebound of EPSPs and PSs (both up by 70-150%). 2. Post 2-DG long-term potentiation (2-DG-LTP) is prevented by block of N-methyl-D-aspartate (NMDA) receptors (NMDARs). Though 2-DG-LTP is normally expressed by other receptors, in presence of picrotoxin 2-DG causes similar LTP of NMDAR-mediated EPSPs. 3. Stimulation at 1 s-1 fully depotentiates 2-DG-LTP. 4. Unlike tetanic LTP, 2-DG-LTP is not pathway-specific, is not occluded by a preceding tetanic LTP (or vice versa) and is insensitive to block of NO synthesis. 5. Hypoglycemic states may have long-lasting after-effects on cerebral synaptic function.     

Increased susceptibility to induction of long-term depression and long-term potentiation reversal during aging

Homosynaptic long-term depression (LTD) and reversal of long-term potentiation (LTP) were examined extracellularly at CA3-CA1 synapses in stratum radiatum of slices from adult (6-9 months) and aged (20-24 months) Fischer 344 rats. Prolonged low-frequency stimulation (LFS) (900 pulses/1 Hz) of the Schaffer collaterals depressed the initial slope of the excitatory postsynaptic potential (EPSP) in aged but not adult rats. LTD at aged synapses was pathway-specific, persistent, and sensitive to the NMDA receptor antagonist DL-2-amino-5-phosphonopentanoic acid (AP5). Adult slices exhibited AP5-sensitive LTD in high [Ca2+] medium, whereas LTD in aged slices was blocked by high [Mg2+], suggesting that differences in Ca2+ regulation may underlie susceptibility to LTD. Despite age-related differences in LTD induction, no age difference in LTP magnitude was revealed. Additionally, LFS delivered 60 min after LTP induction resulted in similar LTP reversal for both age groups. Susceptibility differences to LTP reversal were indicated after multiple short-duration LFS bursts (30 pulses/1 Hz), with each burst separated by 10 min. Aged synapses exhibited significant reversal after a single burst and complete reversal after three LFS episodes. In adult slices, LTP reversal appeared after the fourth burst, and at no time was LTP depressed to initial baseline levels. This study provides the first characterization of homosynaptic LTD/LTP reversal in the aged animal and demonstrates that one form of plasticity, depression attributable to LFS, is increased during aging.     

Synaptic modifications in cultured hippocampal neurons: dependence on spike timing, synaptic strength, and postsynaptic cell type

In cultures of dissociated rat hippocampal neurons, persistent potentiation and depression of glutamatergic synapses were induced by correlated spiking of presynaptic and postsynaptic neurons. The relative timing between the presynaptic and postsynaptic spiking determined the direction and the extent of synaptic changes. Repetitive postsynaptic spiking within a time window of 20 msec after presynaptic activation resulted in long-term potentiation (LTP), whereas postsynaptic spiking within a window of 20 msec before the repetitive presynaptic activation led to long-term depression (LTD). Significant LTP occurred only at synapses with relatively low initial strength, whereas the extent of LTD did not show obvious dependence on the initial synaptic strength. Both LTP and LTD depended on the activation of NMDA receptors and were absent in cases in which the postsynaptic neurons were GABAergic in nature. Blockade of L-type calcium channels with nimodipine abolished the induction of LTD and reduced the extent of LTP. These results underscore the importance of precise spike timing, synaptic strength, and postsynaptic cell type in the activity-induced modification of central synapses and suggest that Hebb's rule may need to incorporate a quantitative consideration of spike timing that reflects the narrow and asymmetric window for the induction of synaptic modification.     

L-Type calcium channels are required for one form of hippocampal mossy fiber LTP

The requirement of postsynaptic calcium influx via L-type channels for the induction of long-term potentiation (LTP) of mossy fiber input to CA3 pyramidal neurons was tested for two different patterns of stimulation. Two types of LTP-inducing stimuli were used based on the suggestion that one of them, brief high-frequency stimulation (B-HFS), induces LTP postsynaptically, whereas the other pattern, long high-frequency stimulation (L-HFS), induces mossy fiber LTP presynaptically. To test whether or not calcium influx into CA3 pyramidal neurons is necessary for LTP induced by either pattern of stimulation, nimodipine, a L-type calcium channel antagonist, was added during stimulation. In these experiments nimodipine blocked the induction of mossy fiber LTP when B-HFS was given [34 +/- 5% (mean +/- SE) increase in control versus 7 +/- 4% in nimodipine, P < 0.003]; in contrast, nimodipine did not block the induction of LTP with L-HFS (107 +/- 10% in control vs. 80 +/- 9% in nimodipine, P > 0.05). Administration of nimodipine after the induction of LTP had no effect on the expression of LTP. In addition, B- and L-HFS delivered directly to commissural/associational fibers in stratum radiatum failed to induce a N-methyl--aspartate-independent form of LTP, obviating the possibility that the presumed mossy fiber LTP resulted from potentiation of other synapses. Nimodipine had no effect on calcium transients recorded from mossy fiber presynaptic terminals evoked with the B-HFS paradigm but reduced postsynaptic calcium transients. Our results support the hypothesis that induction of mossy fiber LTP by B-HFS is mediated postsynaptically and requires entry of calcium through L-type channels into CA3 neurons.     

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.     

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.     

Evidence suggesting that gonadal hormones influence benzodiazepine withdrawal-induced weight loss in rats

Long-term potentiation (LTP) of synaptic transmission in the CA1 region of the hippocampus is thought to result from either increased transmitter release, heightened postsynaptic sensitivity, or a combination of the two. We have measured evoked glutamate release from Schaffer collateral/commissural fiber terminals in CA1 by recording synaptically activated glutamate transporter currents in hippocampal astrocytes located in stratum radiatum. Although several manipulations of release probability caused parallel changes in extracellular field potentials and synaptically activated transporter current amplitudes, induction of LTP failed to alter transporter-mediated responses, suggesting that LTP does not alter the amount of glutamate released upon synaptic stimulation.     

Evidence from simultaneous intracellular recordings in rat hippocampal slices that area CA3 pyramidal cells innervate dentate hilar mossy cells

1. Simultaneous intracellular recordings of area CA3 pyramidal cells and dentate hilar "mossy" cells were made in rat hippocampal slices to test the hypothesis that area CA3 pyramidal cells excite mossy cells monosynaptically. Mossy cells and pyramidal cells were differentiated by location and electrophysiological characteristics. When cells were impaled near the border of area CA3 and the hilus, their identity was confirmed morphologically after injection of the marker Neurobiotin. 2. Evidence for monosynaptic excitation of a mossy cell by a pyramidal cell was obtained in 7 of 481 (1.4%) paired recordings. In these cases, a pyramidal cell action potential was followed immediately by a 0.40 to 6.75 (mean, 2.26) mV depolarization in the simultaneously recorded mossy cell (mossy cell membrane potentials, -60 to -70 mV). Given that pyramidal cells used an excitatory amino acid as a neurotransmitter (Cotman and Nadler 1987; Ottersen and Storm-Mathisen 1987) and recordings were made in the presence of the GABAA receptor antagonist bicuculline (25 microM), it is likely that the depolarizations were unitary excitatory postsynaptic potentials (EPSPs). 3. Unitary EPSPs of mossy cells were prone to apparent "failure." The probability of failure was extremely high (up to 0.72; mean = 0.48) if the effects of all presynaptic action potentials were examined, including action potentials triggered inadvertently during other spontaneous EPSPs of the mossy cell. Probability of failure was relatively low (as low as 0; mean = 0.24) if action potentials that occurred during spontaneous activity of the mossy cell were excluded. These data suggest that unitary EPSPs produced by pyramidal cells are strongly affected by concurrent synaptic inputs to the mossy cell. 4. Unitary EPSPs were not clearly affected by manipulation of the mossy cell's membrane potential. This is consistent with the recent report that area CA3 pyramidal cells innervate distal dendrites of mossy cells (Kunkel et al. 1993). Such a distal location also may contribute to the high incidence of apparent failures. 5. Characteristics of unitary EPSPs generated by pyramidal cells were compared with the properties of the unitary EPSPs produced by granule cells. In two slices, pyramidal cell and granule cell inputs to the same mossy cell were compared. In other slices, inputs to different mossy cells were compared. In all experiments, unitary EPSPs produced by granule cells were larger in amplitude but similar in time course to unitary EPSPs produced by pyramidal cells. Probability of failure was lower and paired-pulse facilitation more common among EPSPs triggered by granule cells.(ABSTRACT TRUNCATED AT 400 WORDS)     

Src activation in the induction of long-term potentiation in CA1 hippocampal neurons

Long-term potentiation (LTP) is an activity-dependent strengthening of synaptic efficacy that is considered to be a model of learning and memory. Protein tyrosine phosphorylation is necessary to induce LTP. Here, induction of LTP in CA1 pyramidal cells of rats was prevented by blocking the tyrosine kinase Src, and Src activity was increased by stimulation producing LTP. Directly activating Src in the postsynaptic neuron enhanced excitatory synaptic responses, occluding LTP. Src-induced enhancement of alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) receptor-mediated synaptic responses required raised intracellular Ca2+ and N-methyl-D-aspartate (NMDA) receptors. Thus, Src activation is necessary and sufficient for inducing LTP and may function by up-regulating NMDA receptors.     

Structure-based modeling of the ligand binding domain of the human cell surface receptor CD23 and comparison of two independently derived molecular models

Brief application of tetraethylammonium (TEA) to hippocampal slices causes long-term potentiation (TEA LTP) at synapses of CA1 pyramidal neurons characterized by a long-lasting increase of field excitatory postsynaptic potential (fEPSP) slope and population spike (PS) amplitude. Since this kind of potentiation requires the activation of voltage-dependent calcium channels, we examined the effect of the inorganic calcium channel blocker aluminum, which has been shown to impair tetanus-induced LTP (eLTP). We found that Al inhibited in a concentration-dependent manner both fEPSP slope and PS amplitude potentiation by TEA; 0.68 microgram/ml A1 attenuated TEA LTP, while a complete block of long-lasting potentiation was obtained for 2.7 micrograms/ml Al. Occlusion experiments revealed that both concentrations of Al allowed the induction of eLTP 60 min after TEA/Al exposure. However, longer application (15 min) of 2.7 micrograms/ml Al before the induction of TEA LTP prevented the subsequent induction of eLTP although no significant differences concerning the action on TEA LTP were observed. This indicates a general loss of neuronal plasticity which might be due to progressive neuronal cell damage. Since the effective concentration range of Al is directly comparable to the action of Al on eLTP, our data provide evidence for shared mechanisms of both potentiations. Although based on different induction mechanisms, Ca2+ is assumed to be a general intracellular trigger for both forms of LTP and thus it can be hypothesized that the neurotoxic action of Al is due to interference with Ca(2+)-dependent processes by inhibition of calcium conductances.     

Anoxia-induced LTP of isolated NMDA receptor-mediated synaptic responses

1. The effects of an anoxic-aglycemic episode (1-3 min) on the pharmacologically isolated N-methyl-D-aspartate (NMDA)-mediated responses were examined in CA1 pyramidal hippocampal neurons in vitro. 2. An anoxic-aglycemic episode induced a long term potentiation (LTP) of the NMDA receptor-mediated field excitatory post-synoptic potentials (EPSPs). This LTP, referred to as anoxic LTP, was observed in the presence of 1) a normal Mg2+ concentration [+40.1 +/- 5% (mean +/- SE)], 2) a low Mg2+ concentration (+52.2 +/- 10%), or 3) a Mg2+ free (+49 +/- 11%), 1 h after anoxia. 3. Bath application of D-2-amino-5-phosphonovaleric acid (D-APV, 20 microM, 15-21 min) before, during, and after the anoxic-aglycemic episode, which transiently blocked the synaptic NMDA receptor mediated response, prevented the induction of anoxic LTP. 4. The intracellularly recorded NMDA receptor-mediated EPSP was also persistently potentiated by anoxia-aglycemia (+47 +/- 4%). This potentiation was not associated with changes in membrane potential or input resistance. 5. These findings provide the first evidence that an anoxic-aglycemic episode induces an LTP of NMDA receptor-mediated responses. This potentiation may participate in the cascade of events that lead to delayed neuronal death.     

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.     

Hebbian induction of LTP in visual cortex: perforated patch-clamp study in cultured neurons

1. To see whether presynaptic activation paired with postsynaptic depolarization is necessary for the induction of long-term potentiation (LTP) in visual cortex or whether an activation of postsynaptic receptors in conjunction with depolarization is sufficient, we carried out perforated patch-clamp recordings with nystatin from cultured cortical neurons of rats. 2. Recorded neurons were monosynaptically activated either by electrical stimulation of an adjacent neuron or by direct activation of glutamate on "hot spots" of dendrites through iontophoresis or pressure ejection. In experiments in which cultured neurons were stained immunocytochemically with antibody against synaptophysin after electrophysiological recordings, hot spots were found to correspond to probable synaptic sites. 3. Excitatory postsynaptic currents (EPSCs) evoked by test stimulation applied to the adjacent neuron at 0.1 Hz were recorded at a holding potential of -60 or -70 mV for 5-10 min after an establishment of the whole cell recording configuration. Then, stimulation was paired with postsynaptic depolarization (0 mV for 200 ms) at 1 Hz for 30 or 60 s. LTP of EPSCs was induced in 7 of the 15 cells from which stable recordings were obtained for 18-30 min after pairing. 4. When postsynaptic depolarization was paired with direct glutamate application in the absence of presynaptic stimulation in 12 cells, only 1 showed LTP. Postsynaptic depolarization alone did not induce LTP in any of the six cells tested. Also, presynaptic stimulation alone did not induce LTP in any of the five cells tested. 5. These results suggest that the concurrent activation of presynaptic elements with postsynaptic depolarization is necessary for the induction of LTP in visual cortex.