Active decay of composite excitatory postsynaptic potentials in hippocampal slices from young rats

NMDA receptor dependent synaptic plasticity was examined in hippocampal slices using a novel pharmacological pairing procedure. Field excitatory postsynaptic potentials (EPSPs) were recorded from the CA1 area of slices maintained in a low Mg(2+) solution using a stimulus rate of 0.1-0.2 Hz. The NMDA receptor antagonist 2-amino-5-phosphonovalerate (AP5) was initially included in the perfusion solution to establish baseline recording of isolated AMPA EPSPs. Washing out AP5 led to the expression of composite EPSPs, containing both AMPA and NMDA receptor mediated components. Following an initial, transient potentiation of the AMPA component, the composite responses gradually decayed for several hours, involving AMPA and NMDA components to a similar extent. This decay was input specific and could be terminated at any stage by reapplication of AP5. Subsequent long-term potentiation (LTP) reversed the effect to an extent inversely related to the degree of depression. Experiments to test the interaction with long-term depression (LTD) revealed a significant but incomplete overlap between the two depression processes. In conclusion, pairing synaptic activation at test stimulus frequency with pharmacological unblocking of NMDA receptors allows for expression of composite EPSPs that decay substantially, due to an active mechanism. The underlying process appears to be at least partly distinct from those involved in homosynaptic LTP and LTD.     

Long-term Potentiation of NMDA Receptor-mediated EPSP in Guinea-pig Hippocampal Slices

Hippocampal slices from guinea-pigs were used to examine the long-term potentiation (LTP) of the N-methyl-d-aspartate (NMDA)-mediated excitatory postsynaptic potential (EPSP). Intracellular recordings were performed from CA1 pyramidal neurons in the presence of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 5 - 10 microM) and picrotoxin (50 microM). In these experimental conditions test stimuli applied at low frequency (0.1 Hz) to the Schaffer collateral - commissural pathway evoked a prolonged EPSP (150 - 200 ms). To obtain this CNQX-resistant EPSP, stimulus intensities had to be raised above the level required to evoke an EPSP of comparable amplitude in physiological solution. Tetanic stimulation (two trains of 100 Hz, 1 s every 20 s) led to a potentiation of the CNQX-resistant EPSP, and this potentiated response was abolished with d-(-)-2-amino-5-phosphonovaleric acid (50 microM). The potentiation of the NMDA receptor-mediated EPSP was more pronounced for strong than for weak test stimuli, and was suppressed when test EPSPs were evoked during membrane hyperpolarization. These results suggest that NMDA receptor-mediated responses can undergo LTP, and hence can contribute to the maintenance of LTP.     

Metabotropic glutamate receptors are involved in calcium-induced LTP of AMPA and NMDA receptor-mediated responses in the rat hippocampus

Effects of metabotropic glutamate (mGlu) receptors on calcium-induced long-term potentiation (LTP) of α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA) and N-methyl-d-aspartate (NMDA) receptor-mediated components were investigated in rat hippocampal slices using whole-cell patch-clamp recordings of excitatory postsynaptic currents (EPSCs). Calcium-induced LTP comprises a parallel, long-lasting increase of AMPA and NMDA receptor-mediated components. The calcium-induced LTP of the AMPA receptor-mediated component can be significantly attenuated by the use of a selective NMDA antagonist. (R.S)-α-methyl-4-carboxyphenylglycine (MCPG), a selective antagonist of mGlu receptors, abolished the long-lasting increase of both AMPA and NMDA receptor-mediated components observed in calcium-induced LTP. In current clamp mode, the application of a high calcium alone or Schaffer fiber stimulation alone (20 Hz) only generated a short-term increase in the firing rate of evoked action potentials. Conversely, a long-term increase in the firing rate was observed if Schaffer fiber stimulation (20 Hz) accompanied the perfusion of high calcium. These results suggest that calcium-induced LTP involves a parallel, long-lasting enhancement in ionotropic AMPA and NMDA receptor-mediated components. More importantly, the mGlu receptor plays a critical role in the establishment of both AMPA and NMDA receptor-mediated components underlying calcium-induced LTP. In addition, the present study also described an experimental condition in which the coapplication of the high calcium pulse and Schaffer fiber stimulation (20 Hz) can synergistically elicit a long-term increase of neuronal excitability.     

Effects of the novel NMDA receptor antagonist, CGP 39551, on field potentials and the induction and expression of LTP in the dentate gyrus in vivo.

The effects of the novel competitive N-methyl-D-aspartate (NMDA) receptor antagonist, CGP 39551 [the carboxyethylester of CGP 37849; DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid], on extracellular field potentials and long-term potentiation (LTP) induced in the dentate gyrus by stimulation of the perforant path were studied in anesthetized rats. CGP 39551 attenuated the population spike (PS) and excitatory postsynaptic potential (EPSP) amplitude of dentate field potentials, reduced the NMDA receptor-mediated component of train-evoked burst potentials, and prevented the induction of LTP. The decrease in PS and EPSP amplitude produced by CGP 39551 was observed mainly in non-potentiated synaptic populations; potentiated field potentials were only minimally affected by drug treatment. These results are consistent with receptors may contribute in a tonic manner to the state of dentate granule cell excitability. Finally, the differential modulation of potentiated and non-potentiated synapses by CGP 39551 suggests that a change in some properties of postsynaptic AMPA receptors is involved in the expression of LTP.     

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.     

Afferent high strength tetanizations favour potentiation of the NMDA vs. AMPA receptor-mediated component of field EPSP in CA1 hippocampal slices of rats

Long-term potentiation (LTP) of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor-mediated components of 'dual-component' field excitatory postsynaptic potentials (fEPSP-A and fEPSP-N) was studied in the CA1 stratum radiatum in hippocampal slices of rats. Relative degrees of LTP of these fEPSP components were compared for tetanizations with low and high strengths. Magnitudes of fEPSP-A and fEPSP-N were estimated in parallel with a least-square fitting of a short-latent (0.1-8.8 ms) fragment of evoked responses by a weighted sum of 'basic' fEPSP-A and fEPSP-N, obtained during a short preliminary application of d-2-amino-5-phosphonovalerate (APV). We found that low-strength tetanizations selectively potentiated fEPSP-A, while high strength tetanizations potentiated both fEPSP components. These results demonstrate in the experiments with parallel measurements of fEPSP-A and fEPSP-N that LTP of these components differ depending on the strength of afferent tetanization. Unequal potentiation of the commissural-collateral and excitatory local-circuit synapses, which presumably contain different amounts of the AMPA and NMDA receptors, is discussed as the most probable explanation for these results.     

The Relative Contribution of NMDA Receptor Channels in the Expression of Long-term Potentiation in the Hippocampal CA1 Region

Long-term potentiation (LTP) was studied in the hippocampal CA1 region of guinea-pigs using a solution containing 0.1 mM magnesium and 10 μM of the non- N -methyl- d -aspartate (non-NMDA) antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), leaving an NMDA-mediated field excitatory postsynaptic potential (EPSP). Brief high-frequency afferent tetanization induced a substantial synapse-specific potentiation of the NMDA EPSP with a time course closely resembling that previously described for LTP of the non-NMDA-mediated EPSP. This NMDA EPSP potentiation was occluded by prior induction of LTP in normal solution. Using a solution containing 0.1 mM magnesium and 1 μM CNQX, the EPSP was composed of both a non-NMDA- and an NMDA-mediated component which could be measured separately and in parallel. Manipulations that cause increased transmitter release, such as phorbol ester application and changes in stimulation frequency, enhanced the two measures nearly equally. Afferent tetanization induced an increase of both EPSP components, with a similar time course, the NMDA component showing a relative increase of about one-third of that of the non-NMDA one. These results suggest that, to the extent that LTP is based on an increased release of transmitter, the mechanism exhibits features distinct from those underlying other forms of enhanced release.     

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.     

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.     

Potentiation and depression following stimulus interruption in young rat hippocampi.

We examined the effect of stimulus interruption on dual component field EPSPs in the hippocampal CA1 region. Resuming test stimulation at 0.1 Hz after 10-60 min silent periods led to an increase of the response followed by a decline, involving AMPA and NMDA components to a similar extent. Similar changes were seen when stimulation was initially applied to a naive pathway or the stimulus strength was increased during an experiment. The potentiation of the AMPA response was largely blocked by prior application of the NMDA antagonist AP5 while application of this drug immediately after the initial potentiation prevented the following decline. The results demonstrate that NMDA-dependent potentiation and depression, possibly equivalent to LTP and LTD, can both be induced by the same, very low, test stimulus frequency. Furthermore, the depression appeared to have a longer time window for its induction than the potentiation.     

Synaptic recruitment during long-term potentiation at synapses of the medial perforant pathway in the dentate gyrus of the rat brain

Long-term potentiation (LTP) in synapses of the medial perforant pathway of the rat dentate gyrus has been studied using the whole-cell voltage clamp technique and a standard hippocampal slice preparation. The rate of LTP induction by 2–4 brief trains of stimuli at 100 Hz, paired with postsynaptic depolarization to −20 mV, in individual granule neurons was only 42% but the average magnitude was large. In a representative series of nine experiments the average potentiation was 339% (s.d. 255%). The variable magnitude of LTP appeared to be related to the relative size of the NMDA receptor dependent current in individual neurons. LTP was further characterized by the selective enhancement of the AMPA (but not the NMDA) component in the excitatory synaptic responses. This selective enhancement of the AMPA component and a graphical variance analysis suggest that the large magnitude of LTP in dentate gyrus can be best explained by recruitment of previously silent synapses by a combination of pre- and post-synaptic mechanisms. © 1996 Wiley-Liss, Inc.     

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.     

Comparing long-term depression with pharmacologically induced synaptic attenuations in young rat hippocampi

Field excitatory postsynaptic potentials (EPSPs) were recorded in the CA1 region of hippocampal slices from 12–18-day-old rats. The isolated N-methyl-D-aspartate (NMDA) receptor mediated field EPSP as well as the composite field EPSP of both NMDA and α-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) receptor mediated components were obtained in low Mg²⁺ solutions with 10 μM or 1 μM of the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), respectively. The isolated AMPA receptor mediated field EPSP was obtained either in normal Mg²⁺ solution or in a low Mg²⁺ solution in the presence of the NMDA receptor antagonist D-2-amino-5-phosphonopentanoic acid. The waveforms of the field EPSPs were studied and the effect of long-term depression (LTD) on these waveforms was compared with the effects of several pharmacological agents that attenuate the synaptic efficacy. It was shown that LTD occurred without changes in the waveforms of isolated AMPA and NMDA EPSPs. Reducing the number of release sites by lowering the stimulus strength or reducing the probability of transmitter release by an adenosine agonist N⁶-cyclohexyl-adenosine both mimicked the LTD-induced changes. Partial blockade of the AMPA receptors was also without effect on the waveforms of isolated AMPA EPSPs. In contrast, partial blockade of the NMDA receptors in several different ways resulted in waveform changes. A similar result could be inferred from experiments using composite field EPSPs. The synaptic attenuation caused by a partial blockade of NMDA receptors therefore appears to differ mechanistically from that involved in LTD, arguing against a postsynaptic locus of the modification involved in LTD. However, directly testing for alterations in transmitter release using the open channel blocker of NMDA receptors MK-801 failed in revealing such presynaptic changes during LTD. Our results therefore suggest that LTD might be due to a coordinated pre- and postsynaptic change instead of distinct pre- or postsynaptic modifications. Synapse 26:329–340, 1997. © 1997 Wiley-Liss Inc.     

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)     

Activation of AP5-sensitive NMDA Receptors is Not Required to Induce LTP of Synaptic Transmission in the Lateral Perforant Path

The role of the N-methyl-d-aspartate (NMDA) type of glutamate receptor in long-term potentiation (LTP) of the medial (MPP) and lateral (LPP) divisions of the perforant path - granule cell system was investigated in urethane-anaesthetized rats. A stimulating electrode was positioned in the dorsomedial or ventrolateral aspect of the angular bundle for selective activation of either the MPP or LPP, respectively. A push - pull cannula served to focally perfuse artificial cerebrospinal fluid (ACSF) across the perforant path synaptic zone, while evoked potentials were monitored in the dentate hilus. Identification of LPP and MPP responses was based on (1) differences in population excitatory postsynaptic potential (EPSP) waveform obtained during stimulus depth profiles, and (2) differential sensitivity of evoked EPSPs to the glutamate receptor agonist l-aminophosphonobutyrate (AP4), and the antagonist gamma-d-glutamylglycine (DGG). High-frequency stimulation (400 Hz, 8 bursts of 8 pulses) applied to the lateral and medial perforant path elicited LTP of the EPSP and population spike in rats perfused with standard medium. In the MPP, LTP was almost completely blocked when d-aminophosphonopentanoate (AP5; 100 microM), a selective NMDA receptor antagonist, was perfused during the tetanus. Surprisingly, in the LPP experiments, AP5 did not impair induction of the 'synaptic' EPSP component of LTP. This occurred despite the ability of AP5 to block LTP of the LPP evoked population spike. The results suggest the existence of a novel, NMDA receptor-independent form of synaptic LTP in the lateral perforant path.     

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.     

Postsynaptic, but not presynaptic, activity controls the early time course of long-term potentiation in the dentate gyrus.

The early time course (less than 1 hr) of long-term potentiation (LTP) in the dentate gyrus of the guinea pig hippocampal slice was examined using extracellular recordings from the outer two-thirds of the dendritic layer. LTP was induced by a single brief (2-40 impulses) high-frequency (20-400 Hz) train, or by pairing a single test stimulus with a brief heterosynaptic high-frequency train. The induction of LTP was facilitated by blockade of fast GABAergic postsynaptic inhibition. It was found that, irrespective of induction conditions and the amount of LTP induced, the onset of LTP was characterized by a latency of a few seconds following the induction event, and a rapid 30 sec growth phase. After a 1-2 min period of little or no further growth, LTP decayed but in a highly variable manner, from cases in which more than 60% of the peak value remained 1 hr after the induction to cases in which LTP decayed completely within 10 min. Factors increasing presynaptic activity (frequency or number of afferent stimulations) during the induction event did not affect the relative amount of LTP decay. Repetitive presynaptic activity was found not to be a necessary condition for eliciting long-lasting LTP (greater than 1 hr), as shown by experiments in which a single presynaptic impulse was paired with a brief heterosynaptic train. Factors increasing postsynaptic activity during the induction event, such as increased stimulus intensity, temporal pairing of two weak trains, or reduced postsynaptic inhibition, all reduced the relative amount of LTP decay. Moreover, partial pharmacological blockade of NMDA receptor channels increased the relative amount of decay. In conclusion, the amount of postsynaptic activity and associated NMDA receptor activation during the induction event appeared to be the main factor governing the early stability of LTP in the dentate gyrus.     

Long-term Potentiation in the Striatum is Unmasked by Removing the Voltage-dependent Magnesium Block of NMDA Receptor Channels

We have studied the effects of tetanic stimulation of the corticostriatal pathway on the amplitude of striatal excitatory synaptic potentials. Recordings were obtained from a corticostriatal slice preparation by utilizing both extracellular and intracellular techniques. Under the control condition (1.2 mM external Mg2+), excitatory postsynaptic potentials (EPSPs) evoked by cortical stimulation were reversibly blocked by 10 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an antagonist of dl-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) ionotropic glutamate receptors, while they were not affected by 30 - 50 microM 2-amino-5-phosphonovalerate (APV), an antagonist of N-methyl-d-aspartate (NMDA) glutamate receptors. In the presence of 1.2 mM external Mg2+, tetanic activation of cortical inputs produced long-term depression (LTD) of both extracellularly and intracellularly recorded synaptic potentials. When Mg2+ was removed from the external medium, EPSP amplitude and duration increased. In Mg2+-free medium, cortically evoked EPSPs revealed an APV-sensitive component; in this condition tetanic stimulation produced long-term potentiation (LTP) of synaptic transmission. Incubation of the slices in 30 - 50 microM APV blocked striatal LTP, while it did not affect LTD. In Mg2+-free medium, incubation of the slices in 10 microM CNQX did not block the expression of striatal LTP. Intrinsic membrane properties (membrane potential, input resistance and firing pattern) of striatal neurons were altered neither by tetanic stimuli inducing LTD and LTP, nor by removal of Mg2+ from the external medium. These findings show that repetitive activation of cortical inputs can induce long-term changes of synaptic transmission in the striatum. Under control conditions NMDA receptor channels are inactivated by the voltage-dependent Mg2+ block and repetitive cortical stimulation induces LTD which does not require activation of NMDA channels. Removal of external Mg2+ deinactivates these channels and reveals a component of the EPSP which is potentiated by repetitive activation. Since the striatum has been involved in memory and in the storage of motor skills, LTD and LTP of synaptic transmission in this structure may provide the cellular substrate for motor learning and underlie the physiopathology of some movement disorders.     

Long-term Potentiation and Field EPSPs in the Lateral and Medial Perforant Paths in the Dentate Gyrus In Vitro: a Comparison

The entorhinal cortex projects monosynaptically to the granule cells in the dentate gyrus via the lateral and medial perforant paths. These two subdivisions of the perforant path differ with respect to synaptic properties, and recent studies suggest that they also differ with respect to long-term potentiation (LTP). In the present study, using the in vitro slice preparation of the guinea-pig hippocampus, field excitatory postsynaptic potentials (EPSPs) and LTP in the lateral and medial perforant paths were compared. The two pathways were distinguished on the basis of their different termination in the dendritic layer, their different pharmacology and short-term synaptic facilitation. The field EPSP [obtained in the presence of γ-aminobutyric acid (GABA) A and B receptor antagonists] consisted of a non- N -methyl- d -aspartate (NMDA) component with different time characteristics in the two pathways, the decay being monoexponential in the lateral perforant path and biexponential in the medial one. In addition, the field EPSP in both pathways contained a small NMDA-mediated component that could also be observed after complete blockade of the non-NMDA one. LTP induction in both lateral and medial perforant paths was facilitated by blockade of GABA_A inhibition, showed associative properties, and was blocked by NMDA receptor antagonists. Following the induction event, LTP in both pathways developed to a peak value within 30–40 s, and the stability of LTP was correlated with the amount of postsynaptic, but not presynaptic, activity during the induction event. During blockade of GABA_A inhibition the opioid receptor antagonist naloxone and the β-adrenergic antagonist timolol had no effect on the magnitude or stability of LTP. It is concluded that LTP in the lateral and medial perforant paths does not differ with respect to induction mechanisms and early temporal characteristics.     

Long-Term Potentiation in Hippocampal CA1: Effects of Afterdischarges, NMDA Antagonists, and Anticonvulsants

Long-term potentiation (LTP) of the basal dendritic population excitatory postsynaptic potential (EPSP) in hippocampal CA1 was readily elicited in behaving rats, without afterdischarges (ADs), by θ-frequency-patterned primed bursts (PBs) delivered to the contralateral CA1. A long-lasting postictal potentiation (PIP) was also elicited by high-frequency trains (1 s at 200 Hz), following an AD and a 5- to 10-min depression. The N -methyl- -aspartate (NMDA) antagonist 2-amino-phosphonovalerate was effective in blocking both LTP and PIP. The noncompetitive NMDA antagonist MK801 (0.5 mg/kg ip) attenuated the PB-induced LTP but enhanced PIP. The anticonvulsants phenytoin (40 mg/kg ip) and U54494A (25 or 50 mg/kg ip) had no effects on the LTP induced by a PB but they, like MK801, enhanced PIP to various degrees. The apparent enhancement of PIP by anticonvulsants may be a direct result of shortening the hippocampal AD duration and alleviation of the postictal EPSP depression. It is inferred that the typical hippocampal AD did not induce potentiation, but rather a postictal depression of the EPSP or a suppression of LTP. The mechanism of the postictal depression is likely different from the NMDA receptor-mediated LTP and PIP and it may depend on the AD duration (and perhaps excessive Ca²⁺ influx) but not critically on NMDA receptors.