Different mechanisms may be required for maintenance,of NMDA receptor-dependent and independent forms of long-term potentiation

In hippocampal area CA1, long-term potentiation (LTP) is induced by tetanic stimulation protocols that activate N-methyl-D-aspartate (NMDA) receptors. In addition, some stimulation protocols can induce LTP during NMDA receptor blockade. An initial signal in both NMDA receptor-dependent and independent LTPs is increased intracellular Ca²⁺ concentration in postsynaptic neurons. It therefore seems possible that subsequent steps leading to expression and maintenance of potentiation are shared whether or not LTP is induced through NMDA receptor activation. We tested this hypothesis by applying a broad spectrum protein kinase, inhibitor, previously shown to inhibit NMDA receptor-dependent LTP. In agreement with earlier reports, we found that H-7 inhibited NMDA receptor-dependent LTP when applied either during tetanic stimulation, or beginning 30 min following tetanic stimulation. In contrast, NMDA receptorindependent LTP was not inhibited by H-7 applied during or following tetanic stimulation. We also tested for mutual occlusion between NMDA receptor-dependent and independent LTPs. Although induction of NMDA receptor-independent LTP did not occlude later induction of NMDA receptor-dependent LTP, induction of NMDA receptordependent LTP did occlude NMDA receptor-independent LTP. While the kinase inhibitor experiment showed a clear difference between NMDA receptor-dependent and independent LTPs, the occlusion experiments suggest an interaction between the signalling pathways for the two LTPs. © 1995 Wiley-Liss, Inc.     

The role of NMDA receptors in long-term potentiation (LTP) and depression (LTD) in rat visual cortex.

The purpose of the present study was to improve our understanding of the role of NMDA receptors in neocortical synaptic plasticity. In slices of rat visual cortex the field potential elicited in layer III in response to white matter stimulation consisted of two components with peak latencies at 5-8 ms (EPSP1) and 12-19 ms (EPSP2). EPSP2 appeared to be polysynaptic since it did not follow stimulation at 0.5 Hz. EPSP1 consisted of both kainate/AMPA and NMDA receptor activity, as revealed by bath application of DNQX and APV. EPSP2 displayed a variable sensitivity to bath-applied APV. Tetanic stimulation of the white matter in normal medium consistently induced long-term potentiation of EPSP1. In the presence of APV, LTP of EPSP1 was induced only when EPSP2 was still present, while there was no change, or LTD was induced, when EPSP2 was completely blocked by APV. In rat visual cortex, blockade of NMDA receptor participation in the postsynaptic response to tetanic stimulation reduces the probability for LTP induction but does not necessarily prevent LTP; synaptic strength may still change in either direction depending, in part, on factors affecting the magnitude of postsynaptic depolarization during tetanus.     

Interferon-alpha inhibits long-term potentiation and unmasks a long-term depression in the rat hippocampus

Interferons (IFN) appear to have various neuromodulatory actions. Here, we characterized the actions of IFN-alpha on the electrophysiological properties of CA1 hippocampal neurons using intracellular recordings. Superfusion of this cytokine did not alter the resting membrane potential, cell input resistance, action potentials, nor GABA-mediated fast synaptic potentials. IFN-alpha inhibited glutamate-mediated excitatory postsynaptic potentials (gEPSPs) and reversed or prevented long-term potentiation (LTP) induced by high-frequency tetanic stimulation. IFN-alpha reduced gEPSP amplitude far below its control value. Only a short-term potentiation (STP) was observed when either IFN-alpha or D-2-amino-5-phosphonovalerato (APV; NMDA receptor antagonist) were present during tetanic stimulation. After this STP in presence of APV, IFN-alpha had no effect on gEPSPs. APV had no effect on LTP when applied after tetanic stimulation and did also not prevent IFN-alpha effect on LTP. Genistein (a tyrosine kinase inhibitor) or heat inactivation prevented IFN-alpha effects. IFN-alpha also decreased the depolarization induced by local application of glutamate but did not modify those induced by NMDA. Similarly, IFN-alpha reversed the potentiation (induced by tetanic stimulation) of glutamate-induced depolarizations. IFN-alpha did not affect long-term depression (LTD) induced by low-frequency tetanic stimulation. In conclusion, IFN-alpha-induced inhibition of LTP is, at least in part, mediated by a postsynaptic effect, by tyrosine kinase activity, and by non-NMDA glutamate receptors. Inhibition of LTP by IFN-alpha unmasks LTD which is induced by the same high-frequency tetanic stimulation.     

Factors governing the potentiation of NMDA receptor-mediated responses in hippocampus.

A modified medium containing an AMPA receptor antagonist and low concentrations of magnesium was used to investigate the factors governing the potentiation of synaptic responses mediated by NMDA receptors. When long-term potentiation (LTP) was induced in standard medium and NMDA responses were analyzed by changing to the modified medium, no statistically significant differences were observed between potentiated and control pathways. Returning the slices to the standard medium showed that LTP was still present, indicating that the potentiation effect was not reversed by the modified medium. High-frequency stimulation applied in the modified medium produced an enhancement of synaptic responses, but this was not occluded by prior potentiation in standard medium. The degree of potentiation induced in the modified medium and expressed by NMDA responses was larger in the presence than in the absence of inhibition and, unlike LTP, was proportionately larger when recorded in the stratum pyramidale than in the stratum radiatum. These results indicate that the potentiation of NMDA receptor-mediated responses triggered by high-frequency stimulation applied in modified medium differs in several respects from the LTP induced in standard conditions. They confirm that LTP is expressed to a markedly different degree by NMDA and non-NMDA receptors and suggest that events that do not necessarily accompany LTP affect the potentiation of NMDA receptor-dependent synaptic responses.     

NMDA receptor blockade prevents LTD, but not LTP induction by intracellular tetanization

Intracellular tetanization, the activation of a postsynaptic cell without concomitant presynaptic stimulation, was applied to layer II/III pyramidal cells in slices of rat visual cortex. In standard extracellular medium, intracellular tetanization led to LTP (21 of 43 inputs) or LTD (14 of 43 inputs), the direction of the amplitude change depending on initial paired-pulse facilitation (PPF) ratio: inputs with high initial PPF ratio were usually potentiated, and inputs with initially low PPF were most often depressed or did not change. When applied during blockade of NMDA receptors (50 microM APV), intracellular tetanization failed to induce LTD, but was still capable of inducing LTP (14 of 26 inputs). Although LTP could occur in inputs with both, low and high initial PPF ratio, the correlation between the amplitude change and initial PPF ratio remained: potentiation was stronger in inputs with initially higher PPF. These data suggest that intracellular tetanization activated simultaneously NMDA receptor-dependent LTD mechanisms and NMDA receptor-independent LTP mechanisms, the final change of synaptic gain depending on their balance.     

The Involvement of N-Methyl-D-Aspartate Receptors in Induction and Maintenance of Long-Term Potentiation in Rat Visual Cortex

Pyramidal neurons from layers II and III of rat visual cortex slices were studied with intracellular recordings. The involvement of N-methyl-D-aspartate (NMDA) receptors was investigated: (1) in the synaptic response to white matter stimulation; (2) in the induction of long-term potentiation (LTP); and (3) in the maintenance of LTP. Bath application of 25 microM of 2-amino-5-phosphonovalerate (APV), an NMDA receptor antagonist, caused a slight (< 10%) reduction of the amplitude of the synaptic response elicited by white matter stimulation. The APV-sensitive excitatory postsynaptic potential (EPSP) had a longer peak latency and duration than the APV-resistant EPSP. Bath application of 10 microM of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA glutamate receptor antagonist, revealed a CNQX-resistant EPSP in response to white matter stimulation which was APV-sensitive. The time course of the CNQX-resistant EPSP was similar to that of the APV-sensitive EPSP and its onset latency was similar to that of the synaptic response in normal medium. Bath application of the GABA-A antagonist bicuculline (0.1 to 0.5 microM) led to a progressive enhancement of the amplitude of the APV-sensitive EPSP. At bicuculline concentrations above 0.3 microM the amplitude of this EPSP increased with membrane depolarization as was the case for the CNQX-resistant EPSP implying that the NMDA receptors were located on the recorded neuron. The susceptibility of the cells to undergo LTP was tested at various concentrations of bicuculline. The effectiveness of bicuculline treatment was quantified by comparing the amplitudes of the synaptic response to just subthreshold stimuli at two post-stimulus delays: (i) at 22 ms, which corresponds to the time to peak of both the initial inhibitory postsynaptic potential and the APV-sensitive EPSP; and (ii) at 8 - 11 ms post-stimulus, which corresponds to the peak of the postsynaptic potential (PSP) in normal medium. Bath application of APV, 20 min after the conditioning tetanus, allowed the authors to measure the amplitude of the APV-sensitive EPSP in the potentiated response. In normal medium, the ratio of the late over the early PSP amplitude was 33.6 +/- 4.1% and tetanic stimulation failed to induce LTP. The conditions remained the same at bicuculline concentrations of 0.1 to 0.2 microM. At higher concentrations of bicuculline the amplitude ratio of late versus early PSP increased and tetanic stimulation induced LTP. In cells, in which bicuculline had caused small ratio increases, only the APV-sensitive EPSP underwent LTP. In cells in which bicuculline had caused large ratio changes, both the APV-resistant and the APV-sensitive EPSP showed LTP. Together with the previous finding that blockade of NMDA receptors prevents LTP (Artola and Singer, 1987) these results suggest that there is a threshold for LTP induction, which is only reached if NMDA receptor-gated channels are sufficiently activated. The data indicate further that the NMDA receptor-mediated EPSP is itself susceptible to LTP whereby its LTP threshold is lower than that of the APV-resistant EPSP. Given the different LTP thresholds of the APV-resistant and APV-sensitive EPSPs, the possibility is raised that their potentiation depends on different mechanisms.     

Interferon-α inhibits long-term potentiation and unmasks a long-term depression in the rat hippocampus

Interferons (IFN) appear to have various neuromodulatory actions. Here, we characterized the actions of IFN-α on the electrophysiological properties of CA1 hippocampal neurons using intracellular recordings. Superfusion of this cytokine did not alter the resting membrane potential, cell input resistance, action potentials, nor GABA-mediated fast synaptic potentials. IFN-α inhibited glutamate-mediated excitatory postsynaptic potentials (gEPSPs) and reversed or prevented long-term potentiation (LTP) induced by high-frequency tetanic stimulation. IFN-α reduced gEPSP amplitude far below its control value. Only a short-term potentiation (STP) was observed when either IFN-α or -2-amino-5-phosphonovalerato (APV; NMDA receptor antagonist) were present during tetanic stimulation. After this STP in presence of APV, IFN-α had no effect on gEPSPs. APV had no effect on LTP when applied after tetanic stimulation and did also not prevent IFN-α effect on LTP. Genistein (a tyrosine kinase inhibitor) or heat inactivation prevented IFN-α effects. IFN-α also decreased the depolarization induced by local application of glutamate but did not modify those induced by NMDA. Similarly, IFN-α reversed the potentiation (induced by tetanic stimulation) of glutamate-induced depolarizations. IFN-α did not affect long-term depression (LTD) induced by low-frequency tetanic stimulation. In conclusion, IFN-α-induced inhibition of LTP is, at least in part, mediated by a postsynaptic effect, by tyrosine kinase activity, and by non-NMDA glutamate receptors. Inhibition of LTP by IFN-α unmasks LTD which is induced by the same high-frequency tetanic stimulation.     

Developmental changes in the susceptibility to long-term potentiation of neurones in rat visual cortex slices.

We investigated with intracellular recordings from rat visual cortex slices whether the susceptibility to undergo long-term potentiation (LTP) is age-dependent and whether it is correlated with the expression of synaptic responses mediated by N-methyl-D-aspartate (NMDA) receptors. Test and tetanic stimuli were applied to the white matter and post-tetanic modifications of the amplitude of postsynaptic potentials (PSPs) were assessed in regular spiking cells of supragranular layers. At 2 weeks of age, the amplitudes of early (8-10 ms post-stimulus) and late (20 ms post-stimulus) PSP-components increased after tetanic stimulation to 137.1 +/- 13.4% and 141.3 +/- 12.1% of the pretetanic controls, respectively. At 3 weeks, potentiation of both PSP-components was less pronounced but still significant, the late component being on average more potentiated than the early one. At 4 weeks, PSPs were no longer potentiated. Bath application of 25 microM DL-2-amino-5-phosphonovalerate (APV), an NMDA receptor antagonist, blocked LTP induction both at 2 and at 3 weeks. We also studied developmental changes of two synaptic responses known to influence the susceptibility of cortical neurones to LTP, the NMDA receptor-mediated excitatory PSP (EPSP) and the initial inhibitory PSP (iIPSP). The amplitude of the APV-sensitive EPSP decreased with age and reached adult values in 4-week-old animals. The iIPSPs were pronounced already at 2 weeks and showed no marked change during further development. The results suggest a close correlation between the susceptibility to undergo LTP and the extent to which NMDA receptor-gated conductances contribute to the synaptic response.(ABSTRACT TRUNCATED AT 250 WORDS)     

Requirement of appropriate glutamate concentrations in the synaptic cleft for hippocampal LTP induction

Although glutamate transporters maintain low extracellular levels of the excitatory neurotransmitter glutamate in the nervous system, little is known about their roles in synaptic plasticity. Here, using knockout mice lacking GLT-1, that is the most abundant glial subtype of glutamate transporters, we showed that long-term potentiation (LTP) induced by tetanic stimulation in mutant mice was impaired in the hippocampal CA1 region. When tetanic stimulation was applied in the presence of low concentrations of an N-methyl-D-aspartate (NMDA) receptor antagonist, the impairment was overcome. Consistent with these results, the increased glutamate in the synaptic cleft of mutant mice preferentially activated NMDA receptors. Furthermore, analyses of mutant mice revealed that the magnitude of NMDA receptor-dependent transient synaptic potentiation during low-frequency stimulation depended on the concentration of glutamate in the synaptic cleft. These findings suggest that GLT-1 plays critical roles in LTP induction, as well as in short-term potentiation, through regulation of extracellular levels of glutamate, which enables appropriate NMDA receptor activation.     

Synaptic modulation of N-methyl-D-aspartate receptor mediated responses in hippocampus

Low magnesium medium and the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5) were used to analyze the effect of several manipulations on the component of excitatory postsynaptic potentials (EPSPs) mediated by activation of NMDA receptors in area CA1 of hippocampal slices. The D-AP5 sensitive component of synaptic responses was characterized by a marked sensitivity to changes in extracellular magnesium and calcium concentrations. In both cases the changes in D-AP5 sensitive responses were considerably larger than those in non-NMDA-dependent potentials. Similarly, frequency facilitation, which is due to a transient increase in release, was accompanied by a greater enhancement of NMDA than non-NMDA receptor-mediated components. The degree of paired-pulse facilitation observed with D-AP5 sensitive responses was magnesium-dependent between concentrations of 0.05 and 0.5 mM, an effect not seen with control potentials. Intracellular injections of hyperpolarizing current pulses differentially affected NMDA and non-NMDA receptor-mediated components. Taken together, these results indicate that changes in the amount of transmitter release may affect to a greater degree NMDA than non-NMDA receptor-mediated components of synaptic responses, probably because of the voltage-sensitive blockade by magnesium of the NMDA receptors. In contrast, induction of long-term potentiation (LTP) by high frequency stimulation produced a larger increase in non-NMDA as opposed to NMDA receptor-dependent responses, a result that does not support the idea that an increase in transmitter release is responsible for LTP.     

Entorhinal cortex long-term potentiation evoked by theta-patterned stimulation of associative fibers in the isolated in vitro guinea pig brain

Long-term potentiation (LTP) induced in the lateral entorhinal cortex by theta-patterned tetanic stimulation of the piriform cortex was analyzed in the isolated guinea pig brain maintained in vitro. Monosynaptic excitatory postsynaptic potentials (EPSPs) evoked by stimulation of the piriform cortex are composed of an early and late component selectively blocked bynon-N-methyl-d-aspartate (non-NMDA) and NMDA receptor antagonists, respectively. LTP induction was dependent on NMDA receptor activation, being blocked by perfusing the preparation with 2-amino-5-phosphonovalerate (AP-5). LTP was expressed through synaptic enhancement of both early non-NMDA and late, possibly NMDA receptor-mediated responses.     

Contribution of NMDA receptor channels to the expression of LTP in the hippocampal dentate gyrus

The role of glutamatergic NMDA receptor channels (NMDARs) in the induction of long-term potentiation (LTP) has been well established. In contrast, whether or not NMDARs contribute to the expression of LTP has been an issue of debate. In this study, we investigated the contribution of NMDARs to LTP expression in the hippocampal dentate gyrus (DG) by stimulating perforant path afferents with short bursts of pulses delivered at a moderate frequency (40 Hz), instead of using the traditional protocol of a single stimulus at a low frequency (<0.1 Hz). The synaptic summation provided by the "burst" protocol enabled us to measure the NMDAR-mediated component of synaptic responses (NMDA component), defined as the NMDAR antagonist D-2-amino-5-phosphonovalerate (APV2+)-sensitive component, in the presence of physiological concentrations of Mg (1 mM). Intracellular recordings were obtained from DG granule cells of rabbit hippocampal slices, and excitatory postsynaptic potentials (EPSPs) were measured in terms of the integrated area of their profiles. At 40 Hz, frequency facilitation of the evoked EPSPs was observed. The NMDA component gradually increased during the five-pulse train and frequency facilitation was significantly reduced after the application of APV. We tested the hypothesis that NMDARs undergo potentiation in LTP by comparing the NMDA/non-NMDA ratio of the synaptic responses in control and LTP groups. An increase in the ratio was observed in the LTP group, strongly suggesting potentiation of NMDARs. To infer changes in conductance at individual synapses based on EPSPs recorded at the soma, we constructed a compartmental model of a morphologically reconstructed DG granule cell. The effect on the NMDA/non-NMDA ratio of changes in AMPA and NMDA component synaptic conductance, and of differences in the distribution of activated synapses, was studied with computer simulations. The results confirmed that NMDARs are potentiated after the induction of LTP and contribute significantly to the expression of potentiation under physiological conditions.     

PKC activation rescues LTP from NMDA receptor blockade

It has been proposed that a critical step in long-term potentiation (LTP) expression is the activation of presynaptic protein kinase C (PKC) after activation of postsynaptic NMDA receptors. A prediction from this "synaptic dialogue" hypothesis (Routtenberg, Trends Neurosci 1999;22:255-256) is that the well-known blockade of LTP by NMDA receptor antagonists would be rescued by direct activation of PKC. To test this prediction we recorded extracellular EPSPs in the molecular layer of the dentate gyrus (DG) in the intact, anesthetized mouse after stimulation of the perforant path. Three experimental series were performed in which tetanization was applied after continuous infusion of 1) vehicle, 2) NMDA receptor antagonist dl-2-amino-5-phosphonovaleric acid (APV) (2.5+/-1.0 nmol), or 3) both APV and then PKC activator 4-beta-phorbol-12,13-dibutyrate (PDBu, 9.0+/-1.0 pmol). LTP was reliably induced in the first series (124+/-5%, N = 6; 2.5 h after the tetanus), suppressed by APV in the second series (95+/-18%, N = 4), and restored in the third series (121+/-13%, N = 5). Decreased paired-pulse facilitation, an index of presynaptic involvement in LTP expression, was observed after tetanization in the first and third series, but not in the second series. Blockade of LTP by NMDA receptor antagonists that can be overridden by presynaptic activation of PKC is thus consistent with the proposed hypothesis. As LTP is rescued after NMDA receptor blockade in transgenic mice overexpressing growth-associated presynaptic protein GAP-43, we suppose that this protein is one of the presynaptic targets of PKC activation.     

The NMDA receptor-mediated components of responses evoked by patterned stimulation are not increased by long-term potentiation

The participation of N-methyl-D-aspartate (NMDA) receptors in synaptic transmission before and after induction of long-term potentiation (LTP) was studied in field CA1 of hippocampal slices. NMDA receptor-mediated postsynaptic responses were determined by comparing responses recorded in the presence and absence of the selective antagonist, D-2-amino-5-phosphonopentanoate (D-AP5, 50 microM). In the presence of physiological magnesium concentrations (1 mM), robust D-AP5-sensitive responses could be evoked by high frequency bursts (4 pulses, 100 Hz) when burst stimulation was preceded 200 ms earlier by 'priming' stimulation (2 pulses, 15 ms apart) of a separate input. Induction of LTP resulted in a substantial potentiation (35%) of non-NMDA-mediated responses to primed bursts but not of NMDA-mediated responses. These results suggest that long-term postsynaptic modifications are at least partly responsible for the expression of LTP.     

Simultaneous Expression of Long-term Depression of NMDA and Long-term Potentiation of AMPA Receptor-mediated Synaptic Responses in the CA1 Area of the Kainic Acid-lesioned Hippocampus

This study investigates the plasticity of the excitatory synapses in an experimental model of epilepsy, the kainic acid-lesioned rat hippocampus. Stimulation of afferents in the CA1 area of lesioned hippocampi produced an epileptiform burst of action potentials, with an underlying synaptic potential composed of mixed α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA; 80%) and N -methyl-D-aspartate (NMDA; 20%) receptor-mediated components. Tetanic stimulation yielded a long-term potentiation (LTP) of the mixed AMPA/NMDA receptor-mediated population excitatory postsynaptic potentials. However, the same type of tetanus resulted in a long-term depression (LTD) of pharmacologically isolated NMDA receptor-mediated responses. This LTD occurred independently of the antagonism of AMPA receptors. This suggests that tetanic stimulation produced LTP of AMPA and LTD of NMDA receptor-mediated responses simultaneously. Finally, both LTP and LTD were shown to be NMDA dependent. This property has profound functional implications for the control of excitatory networks in temporal lobe epilepsy. This work was supported by the Wellcome Trust and the Fondation Simone et Cino Del Duca.     

Glutamate receptor changes associated with transient anoxia/hypoglycaemia in hippocampal slice cultures

Transient anoxia/hypoglycaemia in organotypic hippocampal slice cultures, a model of transient brain ischaemia, ultimately results in delayed cell death. Although the mechanisms underlying this delayed death remain unknown, an increase in excitatory drive has been postulated. We report here that transient anoxia/hypoglycaemia in rat hippocampal slice cultures resulted in a 70-80% enhancement of evoked, alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid (AMPA) receptor-mediated, excitatory responses lasting over 60 min. This effect was prevented by blockade of N-methyl-d-aspartate (NMDA) receptors, did not involve changes of paired-pulse facilitation ratio, but was associated with a 50% increase in amplitude, but not frequency, of spontaneous miniature excitatory postsynaptic currents (mEPSCs). Consistent with this, paired recordings revealed the appearance of AMPA receptor-mediated EPSCs at previously silent synapses and occlusion by prior induction of long-term potentiation (LTP). Transient anoxia/hypoglycaemia further resulted in a 63% potentiation of evoked NMDA receptor-dependent synaptic responses, accounting for the 20% increase in ratio of AMPA to NMDA responses. No change in rectification properties of AMPA receptor-mediated currents could be detected within the first hour following anoxia/hypoglycaemia-induced potentiation. Western blot analyses of slice cultures exposed to either control conditions or a short anoxia/hypoglycaemia revealed a marked, 50-70% increase of GluR1, GluR2/3 and NR1 subunits 1 h, but not 15 min, after the anoxic/hypoglycaemic episode. This increase was blocked by an inhibitor of protein synthesis. Together these results indicate that a transient anoxia/hypoglycaemia is associated with a marked enhancement of excitatory transmission sharing similarities with the mechanisms underlying LTP, and is correlated with an increased synthesis of excitatory receptor subunits.     

NMDA Receptor-dependent Transient Homo- and Heterosynaptic Depression in Picrotoxin-treated Hippocampal Slices

Extracellular recording was used to study the effects of high-frequency (tetanic) stimulation on excitatory synaptic transmission in the CA1 region of rat hippocampal slices in the presence of the _γ-aminobutyric acid (GABA) type A antagonist, picrotoxin (50 _γM). Under these conditions tetanic stimulation (100 Hz, 1 s) at the test intensity resulted in homosynaptic long-term potentiation (LTP). In contrast, tetanic stimulation of higher intensity (100 Hz, 1 s, double test intensity) resulted in homo- and heterosynaptic depression which recovered within 45 min. A transient (1–3 min) negative shift in DC potential and a transient (5–10 min) depression of the homosynaptic fibre volley occurred immediately following the higher intensity tetanus. The DC shift, induction of homo- and heterosynaptic depression and depression of the fibre volley were reversibly prevented by the N -methyl- d -aspartate (NMDA) receptor antagonist, d -2-amino-5-phosphonopentanoate (AP5; 20 _γM) but were not prevented by a variety of L-type calcium channel antagonists. Transient (30 - 45 min) synaptic depression of pharmacologically isolated NMDA receptor-mediated field excitatory postsynaptic potentials also occurred following tetanic stimulation (100 Hz, 1 s) at double test intensity. These results demonstrate an NMDA receptor-dependent form of reversible synaptic depression in the CA1 region of the hippocampus.     

Induction of NMDA receptor-independent long-term potentiation (LTP) in visual cortex of adult rats.

The aim of this study was to examine: (1) whether long-term potentiation (LTP) can be induced in slices from adult rat visual cortex under conditions where inhibition is not antagonized, and (2) the role of N-methyl-D-aspartate (NMDA) receptors in its induction. The field potential elicited in layer III in response to stimulation of the subcortical white matter consisted of a component with peak latency 5-8 ms (N1) and, in most slices, a second component with peak latency 13-19 ms (N2). N1 was generated via both kainate/alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and NMDA receptor activation as revealed by bath application of 6,7-dinitroquinoxaline-2,3-dione (DNQX) and D,L-2-amino-5-phosphonovalerate (APV). N2 was insensitive to APV in most of the slices and was probably polysynaptic since it did not follow stimulation at 0.5 Hz. Tetanic stimulation of the white matter in normal medium induced LTP of N1; in some slices N2 also potentiated. Tetanic stimulation in the presence of APV also induced LTP of N1 and sometimes N2. LTP of N1 induced in APV was of a larger magnitude, and was expressed more quickly than LTP induced in normal medium. It appears that the known reduction of NMDA receptor activity in adult neocortex is accompanied by the development of other mechanisms that maintain synaptic plasticity; these mechanisms seem to operate more efficiently in absence of NMDA receptor activation.     

Chronic liver failure in rats impairs glutamatergic synaptic transmission and long-term potentiation in hippocampus and learning ability

Cognitive function is impaired in patients with liver disease by unknown mechanisms. Long-term potentiation (LTP) in the hippocampus is considered the basis of some forms of learning and memory. The aims of this work were to assess (i) whether chronic liver failure impairs hippocampal LTP; (ii) if this impairment may be due to alterations in glutamatergic neurotransmission, and (iii) if impairment of LTP is associated with reduced learning ability. It is shown that liver failure in Wistar rats induces the following alterations in the hippocampus; (i) alters the phosphorylation of NMDA and AMPA receptors; (ii) reduces the expression of NMDA and AMPA receptors in membranes, (iii) reduces the magnitude of excitatory postsynaptic potentials (EPSPs) induced by activation of NMDA or AMPA receptors, and (iv) impairs NMDA receptor-dependent LTP. Liver failure also impairs learning of the Morris water maze task. Impairment of glutamatergic synaptic transmission and NMDA receptor-mediated responses may be involved in the alterations of cognitive function in patients with liver disease.     

Synaptic plasticity in morphologically identified CA1 stratum radiatum interneurons and giant projection cells

Long-term potentiation (LTP) of synaptic efficacy was examined in interneurons and giant cells in the stratum radiatum region of the hippocampal CA1 subfield. Cells were visually selected using differential interference contrast (DIC) optics and filled with biocytin while being recorded using whole-cell patch-clamp techniques. Electrophysiological criteria, including spike height, width, and degree of spike adaptation shown to sustained depolarization, proved inadequate for differentiating interneurons from giant cells. We found that cells in the stratum radiatum, however, could be reliably differentiated using DIC optics or following intracellular staining. The response of the two cell types to tetanic stimulation further dissociated them. Long-term potentiation, dependent on the activation of NMDAr (N-methyl-D-aspartate receptors), could reliably be induced in interneurons with stimuli administered at 200 Hz, but not 100 Hz. Giant cells, in contrast, exhibited NMDA receptor-dependent LTP in response to 100-Hz stimuli, but not the 200-Hz stimuli. LTP induction in interneurons also appeared temperature-dependent, being much more robust at 34 degrees C than at room temperature. The LTP in both cell types required postsynaptic calcium influx, and was not due to the passive propagation of LTP induction in neighboring pyramidal cells. These results suggest that different cell types within the hippocampal formation may preferentially alter synaptic connectivity in a frequency-specific manner.