Selective enhancement of non-NMDA receptor-mediated responses following induction of long-term potentiation in entorhinal cortex

The contribution of NMDA receptors to the expression of long-term potentiation (LTP) is controversial. In entorhinal cortex (EC) previous studies reported either that LTP was exclusively expressed through NMDA receptors or that both NMDA and non-NMDA receptors were involved in LTP expression. To reexamine this issue, horizontal entorhinal cortical slices were prepared from adult rats and electrical stimulation was delivered in layer II/III, while field potential recordings were made in layer III. In the standard condition (2.5 mM Mg(++)), LTP was reliably induced by theta burst stimulation, but was blocked by 100 microM D-AP5, an NMDA receptor antagonist. This corroborates previous reports that NMDA receptor activation is required for induction of EC LTP. The field potential response was not affected by D-AP5, but completely blocked by 10 microM CNQX, a non-NMDA receptor antagonist. This indicates that the expression of LTP is mediated by non-NMDA receptors in the standard condition. LTP of NMDA receptor-mediated responses was tested by comparing NMDA responses before and after applying theta burst stimulation in medium containing low magnesium (0.4-1 mM). Theta burst stimulation induced 43.2+/-9.7% increase of non-NMDA responses (i.e., AP5-insensitive fast component) but 5.6+/-9.0% decrease of the NMDA receptor component (AP5-sensitive slow component). These results indicate that activation of NMDA receptors is critical for induction of LTP, but LTP expression is mediated by non-NMDA receptors in EC under these experimental conditions.     

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.     

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.     

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.     

GABAB-receptor-mediated inhibition of the N-methyl-D-aspartate component of synaptic transmission in the rat hippocampus.

GABA receptor regulation of NMDA-receptor-mediated synaptic responses was studied in area CA1 of the rat hippocampus using extracellular and intracellular recording techniques. Picrotoxin (PTX) was used to suppress GABAA inhibition and 6,7-dinitroquinoxaline-2,3-dione (DNQX) was used to suppress non-NMDA receptor-mediated responses. In this manner, we were able to avoid the complicating factors caused by potentials induced by other excitatory and inhibitory amino acid receptors. Under these conditions, large NMDA-receptor-mediated EPSPs were observed. When paired stimuli were given at interstimulus intervals from 100 to 400 msec, powerful inhibition of the second response was observed. This inhibition was reversed by the GABAB antagonists phaclofen and 2-hydroxy-saclofen; it was also depressed by removal of Mg2+ from the bath. Examination of non-NMDA receptor-mediated synaptic responses (determined in the presence of D-2-amino-5-phosphonovalerate and PTX) showed no such inhibition, thereby supporting the hypothesis that GABAB inhibition of NMDA EPSPs is postsynaptic. This difference in paired-pulse inhibition of NMDA and non-NMDA EPSPs leads us to conclude that there was no evidence of GABAB-mediated presynaptic inhibition of excitatory transmitter release. Intracellular recordings in the presence of DNQX and PTX revealed a phaclofen-sensitive late IPSP that correlated in time with the period of inhibition of NMDA responses. Taken together, these data suggest that paired-pulse-inhibition of NMDA responses is produced by a GABAB-receptor-mediated hyperpolarization of the postsynaptic membrane, causing an enhanced block of the NMDA channels by Mg2+. Regulation of NMDA-mediated synaptic responses by GABAB receptors constitutes a powerful mechanism for control of a major excitatory system in hippocampal pyramidal cells.     

A test of the spine resistance hypothesis for LTP expression.

Long-term potentiation (LTP) consists of an enhanced response to released transmitter by the quisqualate/AMPA subclass of glutamate receptors with little change in the slower currents generated by the NMDA receptor subclass. Recent computer simulations suggest that a decrease in the resistance of dendritic spines would selectively augment fast synaptic currents and this could produce the pattern of results found with LTP. The present experiments tested this hypothesis by asking whether non-NMDA responses slowed by low temperature to resemble NMDA responses could express LTP. Slow non-NMDA responses recorded at 25 degrees C did express LTP, indicating that the time courses of NMDA responses cannot explain why they do not express LTP. The results, therefore, do not support the hypothesis that spine resistance changes are responsible for the enhanced transmission.     

Further characteristics of long-term potentiation in piriform cortex

Mechanisms for the induction and expression of long-term potentiation (LTP) were studied in slices of piriform cortex. Cooperativity among afferent inputs as a controlling factor for induction of LTP was tested by pairing stimulation of one input that normally does not induce LTP with stimulation of another input. Combined stimulation, given either to two weak inputs with simultaneous bursts or by pairing single pulses with bursts, did effectively induce LTP. Tests for expression of LTP by NMDA vs. non-NMDA receptors indicated that non-NMDA receptor-mediated responses expressed much greater LTP than NMDA receptor-mediated responses. Ratios for paired-pulse facilitation and depression were not altered after induction of LTP. These characteristics are comparable to those exhibited by synapses in the CA1 field of hippocampus. © 1994 Wiley-Liss, Inc.     

Activation of NMDA receptors in hippocampal area CA1 by low and high frequency orthodromic stimulation and their contribution to induction of long-term potentiation

N-methyl-D-aspartate (NMDA) receptors are important in many instances of synaptic plasticity. In hippocampal area CA1, long-term potentiation (LTP) can be induced by both NMDA receptor-dependent and -independent mechanisms. Using intracellular recordings and single-electrode voltage clamp, we isolated and characterized NMDA receptor-mediated synaptic responses. NMDA receptor-mediated responses evoked by low frequency orthodromic stimulation were inhibited in a dose-dependent manner by the competitive antagonist D,L-2-amino-5-phosphonovaleric acid (APV). High frequency (tetanic) stimulation, which facilitates synaptic release of glutamate, failed to overcome the blockade of NMDA receptors by APV. Using extracellular recordings of field potentials, we studied the contribution of NMDA receptors to LTP induced by different patterns of tetanic stimulation. LTP was inhibited in a dose-dependent manner by APV, but was more sensitive to APV than were NMDA receptor-mediated synaptic responses. This most likely reflects a threshold for NMDA receptor activation in LTP induction. A component of LTP that resisted blockade by APV was induced by high (200 Hz), but not low (25 Hz), frequency tetanization. This NMDA receptor-independent component of LTP persisted for > 4 hours and accounted for approximately half the potentiation induced by 200 Hz tetanization. Procedures necessary to induce LTP at the Schaffer collateral/ commissural synapses in area CA1 by both NMDA receptor-dependent and -independent mechanisms are now well characterized. Using the same neuronal population, it will be possible to ask if processes involved in the maintenance of LTP are shared even when LTP is induced through two different mechanisms. © 1994 Wiley-Liss, Inc.     

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.     

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.     

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.     

Delayed postnatal development of NMDA receptor function in medium-sized neurons of the rat striatum

During early postnatal development, the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor plays a dominant role in excitatory amino acid-mediated synaptic transmission in essentially every brain region that has been examined. In contrast, we have found that in the rat striatum, NMDA receptor-mediated current develops later in the medium-sized neurons (MSNs) than currents mediated by activation of non-NMDA receptors. MSNs were identified using infrared video microscopy, and voltage-clamped in a slice preparation using the whole-cell patch-clamp technique. Intrastriatal stimulation was used to evoke excitatory synaptic currents from slices in animals ranging in age from postnatal day (PND) 5 to 60. Though most cells from animals younger than PND 10 failed to respond to synaptic stimulation, postsynaptic responses were occasionally evoked in cells as young as PND 5. Synaptic currents from cells between PNDs 5 and 7 had a significant contribution due to activation of non- NMDA receptors, as evidenced by sensitivity to the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione and rapidly rising and falling response components. The relative contribution of NMDA receptors increased approximately twofold from the first to the third postnatal week; no further change was observed through PND 60. At the same ages that the NMDA receptors contributed maximally to the synaptic current, the decay time constant of the NMDA receptor-mediated current decreased significantly. The increasing weight of NMDA receptor-mediated current may reflect a change in the number of functional receptors at the synapse since there was no apparent change in the voltage dependence of the current. To more completely examine receptor function early in postnatal development, NMDA and kainate were applied either iontophoretically or in the bath. Iontophoretic application of NMDA onto cells obtained from rats between PNDs 3 and 5 only occasionally evoked current, provided that the membrane was held at depolarized potentials to remove the Mg(2+) block. In contrast, application of kainate consistently evoked a response from cells of the same age group. Bath application of the same agonists provided similar results. Taken together, the present experiments demonstrate that striatal non-NMDA receptor-mediated currents are more mature than NMDA receptor-mediated currents early in development.     

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.     

Calcineurin inhibitors, FK506 and cyclosporin A, suppress the NMDA receptor-mediated potentials and LTP, but not depotentiation in the rat hippocampus

The effects of FK506, a Ca²⁺/calmodulin-dependent phosphatase 2B (calcineurin) inhibitor, on the NMDA receptor-mediated potentials and synaptic plasticity were investigated in the CA1 region of the rat hippocampus. Bath application of FK506 (50 μM) produced a 45% inhibition on the NMDA receptor-mediated potentials. FK506 also inhibited the induction of long-term potentiation (LTP), but had no effect on the depotentiation in the CA1 hippocampus. Cyclosporin A (100 μM), another calcineurin inhibitor, mimicked the effects of FK506 on the NMDA responses and synaptic plasticity. These results suggest that FK506 inhibits the activity of NMDA receptors via the involvement of calcineurin. The differential effects of FK506 on LTP and depotentiation may attribute to the partial inhibition on the activity of NMDA receptors and the subsequent attenuation of intracellular Ca²⁺ increase.     

Metabotropic glutamate receptors mediate expression of LTP in slices of rat visual cortex

Long-term-potentiation (LTP) can be induced by application of a standard theta-burst stimulation protocol in slice preparations of the neocortex. This type of LTP is known to be dependent on the activation of NMDA receptors. The present study used specific experimental conditions to evoke a non-NMDA receptor mediated type of LTP. By use of weak theta-burst stimulation (wTBS) we describe a non-NMDA receptor dependent LTP in rat visual cortex in vitro, which is sensitive to an antagonist of metabotropic glutamate receptors (mGluR). In slices of the visual cortex we stimulated ascending inputs in cortical layer IV and recorded extracellular field potentials (FPs) from cortical layers II/III. In disinhibited slices (with 1 microm picrotoxin), a wTBS induced LTP to 138% of control. The expression of this potentiation was insensitive to the NMDA-receptor antagonist, D-AP5, but could be abolished by application of the mGluR antagonist MCPG. These data suggest an NMDA-independent mechanism for LTP induction in the visual cortex which can be observed in layer II/III neurons.     

Crocin antagonizes ethanol inhibition of NMDA receptor-mediated responses in rat hippocampal neurons

We have previously found that crocin (crocetin di-gentiobiose ester) antagonizes the inhibitory effect of ethanol on long-term potentiation in the rat hippocampus in vivo and in vitro. To explore mechanisms underlying the antagonism of crocin against ethanol, we investigated the effects of ethanol and crocin on synaptic potentials mediated by N-methyl-d-aspartate (NMDA) receptors in the dentate gyrus of rat hippocampal slices. Synaptic potential mediated by non-NMDA receptors was recorded in normal medium (1.3 mM Mg²⁺), while NMDA receptor-mediated synaptic potential was isolated in low (0.13 mM) Mg²⁺ medium containing the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (10 μM). Crocin (10 μM) alone did not affect synaptic potentials mediated by non-NMDA nor NMDA receptors. Non-NMDA response was slightly inhibited by 100 mM ethanol, while NMDA response was selectively inhibited by lower concentrations (10–50 mM) of ethanol. Crocin (10 μM) did not affect the inhibition of non-NMDA response by 100 mM ethanol, but significantly blocked the inhibition of NMDA response by 10–50 mM ethanol. In addition, we performed whole-cell patch recording with primary cultured rat hippocampal neurons, and confirmed that crocin blocked ethanol inhibition of inward currents evoked by application of NMDA. These results suggest that crocin specifically antagonizes the inhibitory effect of ethanol on NMDA receptor-mediated responses in hippocampal neurons.     

Long-lasting potentiation of synaptic transmission in the schaffer collateral-commissural pathway of the guinea pig hippocampus by activation of postsynaptic N-methyl-D-aspartate receptor

The effects of short-period (2 min) perfusion of conditioning solution, which contains N-methyl-D-aspartate (NMDA), glycine, and spermine, on the synaptic transmission in the Schaffer collateral-commissural pathway were examined in hippocampal slices with the intracellular recording technique. Long-lasting potentiation of excitatory postsynaptic potentials (EPSPs) was induced (as long as the records lasted, up to 3 h in the longest observation) after membrane potentials of postsynaptic neurons were depolarized by current injection during perfusion of the conditioning solution. D-2-amino-5-phoshonovaleric acid (D-AP5), a specific antagonist of NMDA receptors, block the induction of the long-lasting potentiation by perfusion of NMDA containing solution. This potentiation was accompanied by a decrease in the relative magnitude of EPSP amplitude fluctuation (coefficient of varation, CV). The reciprocals of squared CVs (= mean²/variance) were almost proportional to the magnitude of the potentiation, and the ratios of 1/CV² and the magnitudes of potentiation were not different from those of long-term potentiation (LTP) induced by tetanic stimulation. These findings suggest that long-lasting potentiation is induced solely by activation of postsynaptic NMDA receptors, and transmitter release from presynaptic terminals may be modified by the activation of postsynaptic receptors. © 1993 Wiley-Liss, Inc.     

Induction of long-term potentiation in the basolateral amygdala does not depend on NMDA receptor activation.

Long-term potentiation (LTP) can be induced in the lateral and basolateral amygdala by stimulating synaptic afferents in the external capsule (EC). We examined the sensitivity of amygdaloid LTP to the NMDA receptor antagonist 2-amino-5-phosphonopentanoate (AP5), which is known to block LTP induction in the Schaffer collateral/CA1 synapses in the hippocampus. While relatively high concentrations (100 microM) of DL-AP5 were effective in preventing LTP induction in the lateral and basolateral amygdala in vitro, the same concentrations also significantly depressed synaptic responses to low-frequency stimulation. Furthermore, at 50 microM, a concentration sufficient to block both synaptic responses mediated by NMDA receptors and LTP induction in the hippocampus and neocortex, AP5 did not affect the probability of inducing LTP in the amygdala. Application of 10 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), which blocks non-NMDA excitatory amino acid receptors, reduced the monosynaptic response to EC stimulation by 85%. The remaining CNQX-insensitive response did not appear to be mediated by NMDA-type receptors, since it was not reduced by 50 or 100 microM AP5, and showed none of the voltage sensitivity characteristic of NMDA responses. These data suggest that while the induction of LTP in the amygdala produced by EC stimulation is blocked by high doses of AP5, plasticity at these synapses probably does not require activation of NMDA receptors.     

Enhancement of AMPA-mediated Synaptic Transmission by the Protein Phosphatase Inhibitor Calyculin A in Rat Hippocampal Slices

Using the phosphatase inhibitor calyculin A, we have examined the influence of phosphorylation on synaptic transmission and plasticity in rat CA1 hippocampal slices. Bath application of 0.5 – 1 μM of calyculin A resulted in an increase of 42.6 ±2.9% in synaptic responses. The effect produced by calyculin A was not accompanied by changes in fibre volley, was not associated with changes in paired-pulse facilitation, and could be reproduced by intracellular injection of the compound, thereby indicating a postsynaptic action. Also, the synaptic enhancement produced by calyculin A was expressed only by potentials mediated by amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, but not by the NMDA responses recorded in the presence of the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and low magnesium. The effect of calyculin A could be prevented by KN-62, an inhibitor of calcium/calmodulin-dependent protein kinase II. Long-term potentiation could still be induced in the presence of calyculin A, but the effect of the compound was slightly reduced on potentiated compared with control pathways. These results indicate that calyculin A can selectively increase the efficacy of AMPA receptor-mediated synaptic transmission at excitatory synapses.     

The role of N-methyl-D-aspartate receptors in the generation of short-term potentiation in the rat hippocampus

The effects of stimulus intensity and the N-methyl-D-aspartate (NMDA) antagonist 2-amino-5-phosphonovalerate (AP5) were studied on the induction of short-term potentiation (STP) and long-term potentiation (LTP) in CA1 of the rat hippocampal slice. A tetanus of very weak intensity stimuli produced STP, and also LTP providing the stimuli were applied in the form of a series of high frequency trains rather than one continuous train. Increasing the intensity of the stimuli to just threshold for spike initiation produced larger amplitude STP and LTP. AP5 strongly inhibited the STP as well as the LTP produced by a series of high frequency trains, indicating a large component of this STP was generated by activation of NMDA receptors. A further residual component of STP in AP5, which was associated with a decrease in paired pulse facilitation, is probably generated by a presynaptic increase in the probability of transmitter release.