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G L Collingridge

Publications and source records attributed to G L Collingridge.

At least 73 records · Page 4Linked to original sources
PubMed1996

NMDA receptor dependence of mGlu-mediated depression of synaptic transmission in the CA1 region of the rat hippocampus.

1. The depression of synaptic transmission by the specific metabotropic glutamate receptor (mGlu) agonist (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylate ((1S,3R)-ACPD) was investigated in area CA1 of the hippocampus of 4-10 week old rats, by use of grease-gap and intracellular recording techniques. 2. In the presence of 1 mM Mg2+, (1S,3R)-ACPD was a weak synaptic depressant. In contrast, in the absence of added Mg2+, (1S,3R)-ACPD was much more effective in depressing both the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptor-mediated components of synaptic transmission. At 100 microM, (1S,3R)-ACPD depressed the slope of the field excitatory postsynaptic potential (e.p.s.p.) by 96 +/- 1% (mean +/- s.e.mean; n = 7) compared with 23 +/- 4% in 1 mM Mg(2+)-containing medium (n = 17). 3. The depressant action of 100 microM (1S,3R)-ACPD in Mg(2+)-free medium was reduced from 96 +/- 1 to 46 +/- 6% (n = 7) by the specific NMDA receptor antagonist (R)-2-amino-5-phosphonopentanoate (AP5; 100 microM). 4. Blocking both components of GABA receptor-mediated synaptic transmission with picrotoxin (50 microM) and CGP 55845A (1 microM) in the presence of 1 mM Mg2+ also enhanced the depressant action of (1S,3R)-ACPD (100 microM) from 29 +/- 5 to 67 +/- 6% (n = 6). 5. The actions of (1S,3R)-ACPD, recorded in Mg(2+)-free medium, were antagonized by the mGlu antagonist (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG). Thus, depressions induced by 30 microM (1S,3R)-ACPD were reversed from 48 +/- 4 to 8 +/- 6% (n = 4) by 1 mM (+)-MCPG. 6. In Mg(2+)-free medium, a group I mGlu agonist, (RS)-3, 5-dihydroxyphenylglycine (DHPG; 100 microM) depressed synaptic responses by 74 +/- 2% (n = 18). In contrast, neither the group II agonists ((2S,1'S,2'S)-2-(2'-carboxycyclopropyl)glycine; L-CCG-1; 10 microM; n = 4) and ((2S,1'R,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine; DCG-IV; 100 nM; n = 3) nor the group III agonist ((S)-2-amino-4-phosphonobutanoic acid; L-AP4; 10 microM; n = 4) had any effect. 7. The depolarizing action of (1S,3R)-ACPD, recorded intracellularly, was similar in the presence and absence of Mg(2+)-AP5 did not affect the (1S,3R)-ACPD-induced depolarization in Mg(2+)-free medium. Thus, 50 microM (1S,3R)-ACPD induced depolarizations of 9 +/- 3 mV (n = 5), 10 +/- 2 mV (n = 4) and 8 +/- 2 mV (n = 5) in the three respective conditions. 8. On resetting the membrane potential in the presence of 50 microM (1S,3R)-ACPD to its initial level, the e.p.s.p. amplitude was enhanced by 8 +/- 3% in 1 mM Mg2+ (n = 5) compared with a depression of 37 +/- 11% in the absence of Mg2+ (n = 4). Addition of AP5 prevented the (1S,3R)-ACPD-induced depression of the e.p.s.p. (depression of 4 +/- 5% (n = 5)). 9. It is concluded that activation by group 1 mGlu agonists results in a depression of excitatory synaptic transmission in an NMDA receptor-dependent manner.

Animals↗
PubMed1996

Interactions of 2,3-benzodiazepines and cyclothiazide at AMPA receptors: patch clamp recordings in cultured neurones and area CA1 in hippocampal slices.

1. The 2,3-benzodiazepines GYKI 52466, GYKI 53405 and GYKI 53655 antagonized AMPA-induced currents in cultured superior colliculus neurones in a non use-dependent manner (steady state IC50s: GYKI 52466 9.8 +/- 0.6 microM; GYKI 53405 3.1 +/- 0.6 microM; GYKI 53655 0.8 +/- 0.1 microM). 2. Higher concentrations of all three antagonists slowed the onset kinetics and quickened the offset kinetics of AMPA-induced currents indicative of an allosteric interaction with the AMPA recognition site. 3. Cyclothiazide (3-300 microM) dramatically slowed desensitization of AMPA-induced currents and potentiated steady state currents (EC50 10.0 +/- 2.5 microM) to a much greater degree than peak currents. Both tau on and tau off were also increased by cyclothiazide in a concentration-dependent manner (EC50: tau on 42.1 +/- 4.5 microM; tau off 31.6 +/- 6.6 microM). 4. Cyclothiazide (10-100 microM) shifted the concentration-response curves of the 2,3-benzodiazepines to the right. For example, with 10 microM cyclothiazide the IC50s of GYKI 52466 and GYKI 53405 on steady-state AMPA-induced currents were 57.9 +/- 9.5 and 41.6 +/- 1.5 microM, respectively. 5. GYKI 53405 and GYKI 52466 concentration-dependently reversed the effects of cyclothiazide (100 microM) on offset kinetics (GYKI 53405 IC50 16.6 +/- 4.2 microM). However, the 2,3-benzodiazepines were unable to reintroduce desensitization in the presence of cyclothiazide and even concentration-dependently slowed the onset kinetics of AMPA responses further (GYKI 53405 EC50 8.0 +/- 2.8 microM). 6. GYKI 52466 decreased the peak amplitude of hippocampal area CA1 AMPA receptor-mediated excitatory postsynaptic currents (e.p.s.cs) (IC50 10.8 +/- 0.8 microM) with no apparent effect on response kinetics. Cyclothiazide prolonged the decay time constant of AMPA receptor-mediated e.p.s.cs (EC50 35.7 +/- 6.5 microM) with less pronounced effects in slowing e.p.s.c. onset kinetics and increasing e.p.s.c. amplitude. 7. Cyclothiazide (330 microM) shifted the concentration-response curve for the effects of GYKI 52466 on AMPA receptor-mediated e.p.s.c. peak amplitude to the right (GYKI 52466 IC50 26.9 +/- 9.4 microM). Likewise, GYKI 52466 (30-100 microM)) shifted the concentration-response curve for the effects of cyclothiazide on AMPA receptor-mediated e.p.s.c. decay time constants to the right. 8. In conclusion, cyclothiazide and the 2,3-benzodiazepines seem to bind to different sites on AMPA receptors but exert strong allosteric interactions with one another and with other domains such as the agonist recognition site. The interactions of GYKI 52466 and cyclothiazide on AMPA receptor-mediated e.p.s.cs in area CA1 of hippocampal slices provide evidence that the decay time constant of these synaptic events are not governed by desensitization.

Animals↗
PubMed1995

An investigation of the membrane topology of the ionotropic glutamate receptor subunit GluR1 in a cell-free system.

We have utilized cell-free translation in rabbit-reticulocyte lysate supplemented with canine pancreatic microsomal membranes to study the processing and membrane topology of the rat ionotropic glutamate receptor subunit GluR1. In vitro-synthesized RNA encoding GluR1 was translated to yield a primary translation product with an apparent molecular mass of 99 kDa. In the presence of microsomal membranes this protein was processed to give a band of 107 kDa. Treatment with peptide-N-glycosidase F showed that this increase in molecular mass was due to N-linked glycosylation. Incubation of the processed receptor with proteinase K revealed the presence of a 68 kDa protease-resistant band which decreased to 56 kDa following deglycosylation. A deletion mutant (GluR1M1) lacking the predicted transmembrane domains was fully translocated across the microsomal membrane and protected from the action of the protease. The mutant and wild-type receptor could be immunoprecipitated by anti-peptide antibodies directed against the C-terminus. Following translocation of the wild-type and mutant receptor across the microsomal membrane and treatment with proteinase K the antibody binding to GluR1 was abolished, but was retained for GluR1M1. These data allow identification of the orientation of the N- and C-termini of GluR1 within the microsome; results which are consistent with an extracellular N-terminal and intracellular C-terminal localization following incorporation into the plasma membrane.

Animals↗
PubMed1995

Synaptic potentiation of dual-component excitatory postsynaptic currents in the rat hippocampus.

1. Whole-cell patch-clamp recording has been used to study tetanus-induced synaptic potentiation of dual-component excitatory postsynaptic currents (EPSCs) in the CA1 region of rat hippocampal slices, following blockade of GABAA and GABAB receptor-mediated synaptic inhibition. 2. At a holding potential of -60 mV, the initial slope of the EPSC (between 10 and 60% of maximum amplitude) provided an accurate measurement of the AMPA receptor-mediated component, and the amplitude of the EPSC at a latency of 100 ms provided the best estimate of the size of the NMDA receptor-mediated component. 3. Neurons were voltage clamped for at least 45 min prior to delivery of a tetanus (test intensity, 100 Hz, 1 s). Measurements at 10 and 30 min following the tetanus were used as indications of short-term potentiation (STP) and long-term potentiation (LTP), respectively. One set of neurons were voltage clamped at -60 mV throughout. These neurons could be subdivided into two populations on the basis of whether or not there was LTP (n = 9), or only STP (n = 6), of the AMPA receptor-mediated component. A second set of neurons were voltage clamped at -60 mV for 30 min and then at -50 mV for 15 min before, during and for 30 min following tetanization. In these experiments there was STP but not LTP (n = 8). 4. In all neurons (n = 23), the time course of the potentiation of the NMDA receptor-mediated component paralleled that of the AMPA receptor-mediated component. In addition, potentiation of the NMDA and AMPA receptor-mediated components were of a similar magnitude. 5. These data demonstrate that it is possible to induce LTP by high frequency stimulation after 45 min of whole-cell recording. Under these conditions, there is a parallel potentiation of the AMPA and NMDA receptor-mediated components of dual-component EPSCs. This constitutes the first evidence, from studies of dual-component synaptic responses, which is consistent with a presynaptic locus of expression of tetanus-induced STP and LTP in the hippocampus.

Animals↗
PubMed1995

On the mechanism of long-term potentiation induced by (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) in rat hippocampal slices.

We have reported previously that transient application of a specific metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (ACPD) can induce a slow-onset form of long-term potentiation (LTP) of synaptic transmission in the CA1 region of rat hippocampal slices [Bortolotto Z. A. and Collingridge G. L. (1993) Neuropharmacology 32, 1-9]. Here we have investigated further the mechanisms involved in the induction and expression of ACPD-induced LTP. Unless otherwise stated, field excitatory postsynaptic potentials (EPSPs) were recorded in stratum radiatum in response to low frequency (0.033 Hz stimulation) of the Schaffer collateral-commissural pathway and 10 microM ACPD was added for 20 min to the perfusate. ACPD-induced LTP was still observed following blockade of GABAA receptor-mediated synaptic inhibition using picrotoxin (50 microM) and was not the result of a change in the presynaptic fibre volley. Intracellular recording from area CA1 revealed an increase in the size of the EPSP but no associated change in membrane potential or input resistance. However, ACPD-induced potentiation was never seen when intracellular electrodes contained the Ca(2+)-chelating agent 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA; 0.5 M). In area CA3, ACPD elicited a slow-onset LTP of the intracellularly recorded EPSP, evoked by stimulation of associational fibres. In contrast to area CA1, 10 microM ACPD depolarized CA3 neurones. Unlike certain other forms of tetanus- and chemically-induced potentiation, ACPD-induced LTP was not affected by the L-type Ca2+ channel antagonist nimodipine (50 microM). It was, however, prevented by delivering low frequency stimulation (900 shocks at 1 Hz) immediately following termination of the application of ACPD; an effect which was inhibited by the specific N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonopentanoate (AP5; 50 microM). ACPD failed to induce LTP of pharmacologically-isolated NMDA receptor-mediated EPSPs. The induction of ACPD-induced LTP was blocked by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), in a reversible manner. In slices in which area CA3 had been removed ACPD failed to induce LTP when applied alone or together with AMPA. However, a slow-onset form of LTP was induced, in slices lacking area CA3, when a tetanus (100 Hz, 1 sec) was delivered in the presence of ACPD and 50 microM AP5 (the latter applied to prevent conventional tetanus-induced LTP). ACPD-induced LTP was associated with a parallel increase in the sensitivity of CA1 neurones to AMPA. Considered together, these data suggest that ACPD-induced LTP is due to a direct increase in the AMPA receptor-mediated synaptic conductance and involves postsynaptic induction and expression mechanisms.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1995

Pharmacological evidence for an involvement of group II and group III mGluRs in the presynaptic regulation of excitatory synaptic responses in the CA1 region of rat hippocampal slices.

The actions of four mGluR antagonists, (+)-MCPG, MAP4, MCCG and (S)-4CPG, were evaluated against agonist-induced depressions of synaptic transmission at the Schaffer collateral-commissural pathway in rat hippocampal slices. (+)-MCPG (1 mM) reversed very effectively depressions of field EPSPs induced by (1S,3R)-ACPD and (1S,3S)-ACPD but had weak and variable effects on depressions induced by L-AP4. It had no effect on depressions induced by either (-)-baclofen or carbachol. In contrast, MAP4 (500 microM) reversed very effectively depressions induced by L-AP4 without affecting depressions induced by (1S,3S)-ACPD. MCCG (1 mM) had the opposite activity; it antagonized depressions induced by (1S,3S)-ACPD but not those induced by L-AP4. Finally, (S)-4CPG (1 mM) reversed small depressions of field EPSPs induced by high concentrations (50-100 microM) of (1S,3R)- and (1S,3S)-ACPD, but not L-AP4, whilst having no effect on large depressions induced by 10 microM (1S,3S)-ACPD in voltage-clamped cells. These results confirm and extend the effectiveness and selectivity of (+)-MCPG as an mGluR antagonist. The divergent effects of the group I antagonist, (S)-4CPG, can be explained by an indirect action on postsynaptic receptors which is manifest when high agonist concentrations are used in non-voltage-clamp experiments. The action of MCCG and MAP4 indicates that two pharmacologically-distinct mGluRs, belonging to classes II and III, can regulate synaptic transmission in the CA1 region via presynaptic mechanisms.

Animals↗
PubMed1995

The brain slice preparation: a tribute to the pioneer Henry McIlwain.

Henry McIlwain is usually remembered for his major contributions to the discipline of neurochemistry. He also had a profound influence on electrophysiology by inventing and establishing the brain slice technique. This article describes some of his pioneering studies where he devised ways of preparing, both manually and mechanically (using the McIlwain tissue chopper), viable slices of mammalian cortical tissue and showed how these could be maintained in a brain slice chamber. His work with Choh-Luh Li (Li and McIlwain, 1957) on the first intracellular recording from brain slices and his work with Chosaburo Yamamoto (Yamamoto and McIlwain, 1966) describing the first study of synaptic transmission in brain slices are highlighted. In these studies, McIlwain started the use of brain slices to investigate functional anatomy, to study the effects of hypoxia and hypoglycaemia, to perform quantitative pharmacological analyses and to study synaptic plasticity: investigations which continue today to provide important insights into the functioning of the brain in health and disease.

Animals↗
PubMed1995

Studies on the role of metabotropic glutamate receptors in long-term potentiation: some methodological considerations.

There has been considerable interest recently in trying to elucidate the roles of metabotropic glutamate receptors (mGluRs) in the induction of long-term potentiation (LTP) in area CA1 of rat hippocampal slices. This has come about principally because of the development of specific mGluR agonists and antagonists. Recently we reported that the competitive mGluR antagonist (+)-alpha-methyl-4-carboxyphenylglycine (MCPG) blocks the induction of LTP but not short-term potentiation (STP). We describe here the dose-dependency of the MCPG block; there is no effect at 100 microM while at 200 microM the block of LTP is normally complete but STP is spared. A higher concentration of MCPG (500 microM) has the same effect as 200 microM. We have also reported recently that high-frequency (tetanic) stimulation conditions a pathway such that MCPG fails to block the induction of subsequent LTP. We illustrate here that the conditioning effect of a tetanus lasts at least 6 h. We show how the pathway can be conditioned, without any persistent change in the synaptic response, by delivering tetanic stimulation in the presence of the specific NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (AP5). The pathway can subsequently be deconditioned by delivering low-frequency stimulation (900 shocks at 2 Hz) so that MCPG blocks the induction of subsequent LTP. We also have reported that the specific mGluR agonist 1-aminocyclopentane-(1S,3R)-dicarboxylate (ACPD) can induce LTP without the need for STP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Pharmacology of postsynaptic metabotropic glutamate receptors in rat hippocampal CA1 pyramidal neurones.

1. Activation of metabotropic glutamate receptors (mGluRs) in hippocampal CA1 pyramidal neurones leads to a depolarization, an increase in input resistance and a reduction in spike frequency adaptation (or accommodation). At least eight subtypes of mGluR have been identified which have been divided into three groups based on their biochemical, structural and pharmacological properties. It is unclear to which group the mGluRs which mediate these excitatory effects in hippocampal CA1 pyramidal neurones belong. We have attempted to address this question by using intracellular recording to test the effects of a range of mGluR agonists and antagonists, that exhibit different profiles of subtype specificity, on the excitability of CA1 pyramidal neurones in rat hippocampal slices. 2. (2S, 1'S,2'S)-2-(2'-carboxycyclopropyl)glycine (L-CCG1) caused a reduction in spike frequency adaptation and a depolarization (1-10 mV) associated with an increase in input resistance (10-30%) at concentrations (> or = 50 microM) that have been shown to activate mGluRs in groups I, II and III. Similar effects were observed with concentrations (50-100 microM) of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD) and (1S,3S)-ACPD that exhibit little or no activity at group III mGluRs but which activate groups I and II mGluRs. 3. Inhibition of the release of endogenous neurotransmitters through activation of GABAB receptors, by use of 200 microM (+/-)-baclofen, did not alter the effects of (1S,3R)-ACPD (50-100 microM), (1S,3S)-ACPD (100 microM) or L-CCG1 (100 microM). This suggests that mGluR agonists directly activate CA1 pyramidal neurones. 4. Like these broad spectrum mGluR agonists, the racemic mixture ((SR)-) or resolved (S)-isomer of the selective group I mGluR agonist 3,5-dihydroxyphenylglycine ((SR)-DHPG (50-100 microM) or (S)-DHPG (20-50 microM)) caused a reduction in spike frequency adaptation concomitant with postsynaptic depolarization and an increase in input resistance. In contrast, 2S,1'R,2'R,3'R-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV; 100 microM) and (S)-2-amino-4-phosphonobutanoic acid (L-AP4; 100-500 microM), which selectively activate group II mGluRs and group III mGluRs, respectively, had no effect on the passive membrane properties or spike frequency adaptation of CA1 pyramidal neurones. 5. The mGluR antagonists (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG; 1000 microM) and (S)-4-carboxyphenylglycine ((S)-4CPG; 1000 microM), which block groups I and II mGluRs and group I mGluRs, respectively, had no effect on membrane potential, input resistance or spike frequency adaptation per se. Both of these antagonists inhibited the postsynaptic effects of (1S,3R)-ACPD (50-100 microM), (1S,3S)-ACPD (30-100 microM) and L-CCG1 (50-100 microM). (+)-MCPG also reversed the effects of (SR)-DHPG(75 gM). (The effect of (S)-4CPG was not tested.) Their action was selective in that both antagonists did not reverse the reduction in spike frequency adaptation induced by carbachol (1 microM) or noradrenaline(10 microM) whereas atropine (10 microM) and propranolol (100 microM) did.6 From these data it is concluded that the mGluRs in CAl pyramidal neurones responsible for these excitatory effects are similar to the mGluRs expressed by non-neuronal cells transfected with cDNA encoding group I mGluRs.

Animals↗
PubMed1994

The nitric oxide--cyclic GMP pathway and synaptic depression in rat hippocampal slices.

The ability of exogenous nitric oxide (NO) to modify synaptic transmission was investigated in area CA1 of the rat hippocampal slice. The NO donors S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione (SNOG) depressed field excitatory postsynaptic potentials evoked by low frequency stimulation of the Schaffer collateral-commissural pathway. Upon washout of the NO donors, synaptic transmission rapidly returned to control levels. A similar reversible synaptic depression was produced by SNAP when tetanic stimulation (100 Hz; 1 s) was delivered in its presence. The effect of SNAP was not mimicked by its precursor or breakdown product and was blocked by haemoglobin, indicating that the effect involved NO. Roussin's black salt, a photolabile NO donor, also depressed transiently field excitatory postsynaptic potentials following photolysis. The depression was induced rapidly following a flash of UV light (20 s duration) focused onto the slice using a confocal microscope. The depressant effect of the NO donors on synaptic transmission was mimicked by zaprinast, a specific cGMP-phosphodiesterase inhibitor. Zaprinast depressed to a similar extent both the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate and N-methyl-D-aspartate receptor-mediated components of excitatory postsynaptic currents without affecting passive membrane properties, indicating a presynaptic locus of action. SNAP, SNOG and zaprinast all elevated cGMP levels in rat hippocampal slices. Immunocytochemical staining revealed that the cGMP accumulation was mainly in a network of varicose fibres running throughout the CA1 region, consistent with a presynaptic site of action of NO. We conclude that NO, possibly through activation of guanylate cyclase, may be involved in transient presynaptic depression in the CA1 region of the hippocampus.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1994

A molecular switch activated by metabotropic glutamate receptors regulates induction of long-term potentiation.

Pharmacological studies of long-term potentiation (LTP) in the hippocampus are starting to provide a molecular understanding of synaptic plastic processes which are believed to be important for learning and memory in vertebrates. In the CA1 region of the hippocampus, the synaptic activation of glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype is necessary for the induction of LTP under most experimental conditions. The synaptic activation of metabotropic glutamate receptors (mGluRs) is also needed for the induction of LTP. We now show that the role of mGluRs in the induction of LTP is fundamentally different from that of NMDA receptors. NMDA receptors initiate a molecular event that needs to be triggered each time a tetanus is delivered to induce LTP. In contrast, mGluRs activate a molecular switch which then negates the need for mGluR stimulation during the induction of LTP. This mGluR-activated switch is input-specific and can be turned off by a train of low-frequency stimulation. The molecular switch is a new feature of LTP which has fundamental consequences for our understanding of synaptic plastic mechanisms.

Animals↗
PubMed1994

A comparison of paired-pulsed facilitation of AMPA and NMDA receptor-mediated excitatory postsynaptic currents in the hippocampus.

Paired-pulse facilitation of excitatory synaptic transmission was investigated in the CA1 region of rat hippocampal slices using whole-cell patch-clamp recording. To optimise the measurement of excitatory synaptic transmission, gamma-amino-butyric acid (GABA)-mediated synaptic inhibition was eliminated using both GABAA and GABAB antagonists. Pure alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or N-methyl-D-aspartate (NMDA) receptor-mediated excitatory postsynaptic currents (EPSCs) were then isolated pharmacologically. Paired-pulse facilitation of either AMPA or NMDA receptor-mediated EPSCs (EPSCA and EPSCN, respectively) was investigated using two stimuli of identical strength delivered at intervals of between 25 and 1000 ms. The paired-pulse facilitation profiles of both EPSCA and EPSCN were similar. Paired-pulse facilitation of EPSCA was independent of holding potential. In contrast paired-pulse facilitation of EPSCN was markedly voltage-dependent; maximum facilitation was recorded at hyperpolarised membrane potentials. At positive membrane potentials there was little or no paired-pulse facilitation and, in most neurones, paired-pulse depression was observed. Voltage-dependence of paired-pulse facilitation of EPSCN was similar in the presence of nominal absence of Mg2+ in the bathing medium, and was unaffected by extensive dialysis of neurones with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA). These data are consistent with a presynaptic locus for paired-pulse facilitation of EPSCA. However, paired-pulse facilitation of EPSCN involves postsynaptic factors.

Animals↗
PubMed1994

An investigation of depotentiation of long-term potentiation in the CA1 region of the hippocampus.

We have investigated long-term synaptic depression in the CA1 region of rat hippocampal slices. Prolonged low-frequency stimulation (LFS; 900 stimuli delivered at 2 Hz) of the Schaffer collateral-commissural pathway in naïve slices did not induce long-term depression (LTD) of synaptic transmission. However, if long-term potentiation (LTP) was firstly induced in the pathway then LFS generated an LTD-like effect (i.e. depotentiation of LTP). Depotentiation could be induced 2 h (the longest time studied) after the induction of LTP and was stable for the duration of the experiment (followed for up to 40 min). The induction of depotentiation was not blocked by the N-methyl-D-aspartate receptor antagonist D-2-amino-5-phosphonopentanoate, the L-type voltage-gated Ca2+ channel blocker nimodipine or the nitric oxide synthase inhibitor N omega-nitro-L-arginine. However, the magnitude of depotentiation was reversibly reduced, in a stereoselective manner, by the specific metabotropic glutamate receptor (mGluR) antagonist (+)-alpha-methyl-4-carboxyphenylglycine. These results show that prolonged low frequency stimulation can result in an mGluR-dependent depotentiation of LTP.

2-Amino-5-phosphonovalerate↗
PubMed1994

Activation of the NO-cGMP signalling pathway depresses hippocampal synaptic transmission through an adenosine receptor-dependent mechanism.

Activation of the NO-cGMP pathway or adenosine receptors depresses reversibly synaptic transmission in the hippocampus. Here we demonstrate, using the selective A1 receptor antagonist DPCPX, a convergence in the mechanisms of action of the NO donor SNAP, the cGMP phosphodiesterase inhibitor zaprinast and adenosine.

3',5'-Cyclic-GMP Phosphodiesterases↗