Biomedical subjects

R Anwyl

Publications and source records attributed to R Anwyl.

At least 19 recordsLinked to original sources

PubMed1998

Glucocorticoid receptor and protein/RNA synthesis-dependent mechanisms underlie the control of synaptic plasticity by stress.

Learning and memory are exquisitely sensitive to behavioral stress, but the underlying mechanisms are still poorly understood. Because activity-dependent persistent changes in synaptic strength are believed to mediate memory processes in brain areas such as the hippocampus we have examined the means by which stress affects synaptic plasticity in the CA1 region of the hippocampus of anesthetized rats. Inescapable behavioral stress (placement on an elevated platform for 30 min) switched the direction of plasticity, favoring low frequency stimulation-induced decreases in synaptic transmission (long-term depression, LTD), and opposing the induction of long-term potentiation by high frequency stimulation. We have discovered that glucocorticoid receptor activation mediates these effects of stress on LTD and long-term potentiation in a protein synthesis-dependent manner because they were prevented by the glucocorticoid receptor antagonist RU 38486 and the protein synthesis inhibitor emetine. Consistent with this, the ability of exogenously applied corticosterone in non-stressed rats to mimic the effects of stress on synaptic plasticity was also blocked by these agents. The enablement of low frequency stimulation-induced LTD by both stress and exogenous corticosterone was also blocked by the transcription inhibitor actinomycin D. Thus, naturally occurring synaptic plasticity is liable to be reversed in stressful situations via glucocorticoid receptor activation and mechanisms dependent on the synthesis of new protein and RNA. This indicates that the modulation of hippocampus-mediated learning by acute inescapable stress requires glucocorticoid receptor-dependent initiation of transcription and translation.

Animals↗

PubMed1998

(+)-MCPG blocks induction of LTP in CA1 of rat hippocampus via agonist action at an mGluR group II receptor.

We investigated the effect of metabotropic glutamate receptor (mGluR) ligands on the induction of long-term potentiation (LTP) of field excitatory postsynaptic potentials (EPSPs) in CA1 of rat hippocampus, in particular the manner by which the nonsubtype selective mGluR ligand alpha-methyl-4-carboxyphenylglycine [(+)-MCPG] blocks LTP induction. Normalized control LTP was blocked by (+)-MCPG (250 microM), but not by the mGluRI selective antagonist (S)-4-carboxyphenylglycine (4-CPG), the mGluRII selective antagonist 1/(2S,3S, 4S)-2-methyl-2-(carboxycyclopropyl) glycine (MCCG), or the mGluRIII antagonist (S)-2-amino-2-methyl-4-phosphonobutanoic acid/alpha-methyl (MAP4). In contrast the mGluRII agonist ((1S, 3S)-1-aminocyclopentante-1,3-dicarboxylic acid -(1S,3S)-ACPD-; 10 or 25 microM) completely and consistently blocked LTP. The block of LTP by both (1S,3S)-ACPD and (+)-MCPG could be prevented by preincubation with the mGluRII antagonist MCCG. These studies demonstrate that (+)-MCPG blocks LTP induction through an agonist action at an mGluRII receptor and not through a nonselective antagonist action.

Amino Acids, Dicarboxylic↗

PubMed1997

Block of LTP in rat hippocampus in vivo by beta-amyloid precursor protein fragments.

The effects of beta-amyloid precursor protein (beta-APP) fragments on plasticity of glutamtatergic synaptic transmission were examined in the hippocampus of urethane anaesthetized rats. I.c.v. injection of beta-amyloid (A beta) 1-40 and 1-42 and the C-terminal fragment CT105 greatly shortened the duration of high frequency stimulation-induced long-term potentiation (LTP) of field excitatory postsynaptic potentials in the CA1 area. Whereas in vehicle injected animals LTP was stable over a 5 h recording period, doses of these peptides (A beta 1-40, 0.4 and 3.5 nmol; A beta1-42, 0.01 nmol; CT105, 0.05 nmol) which did not affect baseline synaptic transmission abolished LTP within 3-5 h. The reduced duration of this form of synaptic plasticity may contribute to the cognitive deficits in Alzheimer's disease.

Amyloid beta-Protein Precursor↗

PubMed1997

Stimulation on the positive phase of hippocampal theta rhythm induces long-term potentiation that can Be depotentiated by stimulation on the negative phase in area CA1 in vivo.

Long-term potentiation (LTP) of synaptic transmission induced by high-frequency stimulation (HFS) is considered to be a model for learning processes; however, standard HFS protocols consisting of long trains of HFS are very different from the patterns of spike firing in freely behaving animals. We have investigated the ability of brief bursts of HFS triggered at different phases of background theta rhythm to mimic more natural activity patterns. We show that a single burst of five pulses at 200 Hz given on the positive phase of tail pinch-triggered theta rhythm reliably induced LTP in the stratum radiatum of the hippocampus of urethane-anesthetized rats. Three of these bursts saturated LTP, and 10 bursts occluded the induction of LTP by long trains of HFS. Burst stimulation on the negative phase or at zero phase of theta did not induce LTP or long-term depression. In addition, stimulation with 10 bursts on the negative phase of theta reversed previously established LTP. The results show that the phase of sensory-evoked theta rhythm powerfully regulates the ability of brief HFS bursts to elicit either LTP or depotentiation of synaptic transmission. Furthermore, because complex spike activity of approximately five pulses on the positive phase of theta rhythm can be observed in freely moving rats, LTP induced by the present theta-triggered stimulation protocol might model putative synaptic plastic changes during learning more closely than standard HFS-induced LTP.

Anesthetics, Intravenous↗

PubMed1997

PCCG-IV inhibits the induction of long-term potentiation in the dentate gyrus in vitro.

The effects of two ligands with previously established high and selective potency for metabotropic glutamate receptors (mGlu receptors) group II have been investigated on the high frequency stimulation (HFS) induced long-term potentiation of the field excitatory postsynaptic potential (EPSP) in the dentate gyrus of the rat hippocampus in vitro. The ligands investigated were (2S,1'S,2'S,3'R)-2-(2"-carboxy-3'-phenylcyclopropyl)glycine (PCCG-IV) and (R,S)-alpha-methyl-4-tetrazolylphenylglycine (MTPG). PCCG-IV (10 microM) strongly inhibited the induction of long-term potentiation of the field EPSP by high frequency stimulation. MTPG (50 microM) did not inhibit the induction of long-term potentiation, but prevented the inhibition of long-term potentiation induction by PCCG-IV. The inhibition of long-term potentiation induction by PCCG-IV is suggested to be due to an agonistic action on mGlu receptor group II, probably mGlu3 receptor, as the inhibition of long-term potentiation can be reversed by the application of MTPG, a well-known selective and potent antagonist of mGlu receptor group II.

Alanine↗

PubMed1997

Behavioural stress facilitates the induction of long-term depression in the hippocampus.

The induction of activity-dependent persistent increases in synaptic efficacy, such as long-term potentiation (LTP), is inhibited by behavioural stress. The question arises whether stress also affects the ability to induce persistent decreases in synaptic efficacy, such as long-term depression (LTD). We now report that the induction of stable homosynaptic LTD in the CA1 area of the hippocampus of awake adult rats is facilitated, rather than inhibited, by exposure to mild naturalistic stress. The same stress blocked the induction of LTP. The effects of such stress were short lasting: acclimatization to, or removal from, the conditions that facilitated LTD induction led to a rapid loss of the ability to elicit this form of plasticity. The time window in which LTD could be reliably elicited was prolonged by inducing anaesthesia immediately after the stress. These data reveal that even brief exposure to mild stress can produce a striking shift in the susceptibility to synaptic plasticity in the awake animal.

Animals↗

PubMed1997

Effect of repeated ipsapirone treatment on hippocampal excitatory synaptic transmission in the freely behaving rat: role of 5-HT1A receptors and relationship to anxiolytic effect.

The effects of acute and repeated treatment with the 5-HT1A receptor ligand ipsapirone on hippocampal excitatory synaptic transmission and in an ultrasonic vocalization anxiety test were investigated in the rat. Synaptic responses in the CA1 region of the dorsal hippocampus of alert, freely behaving male Wistar rats were reduced after acute injection of ipsapirone (1 or 2 mg/kg, i.p.). This effect was prevented by pretreatment with the 5-HT1A receptor antagonist WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclo-hexanecarboxamide trihydrochloride, 0.25 or 0.5 mg/kg, i.p.) but not by the 5-HT-depleting agent para-chlorophenylalanine (300 mg/kg per day for 3 days, i.p.). WAY-100635 (0.1-0.3 mg/kg, i.p.) also blocked the acute anti-aversive effects of ipsapirone (3 mg/kg, i.p.) in the anxiety test. Repeated administration of ipsapirone (1 or 2 mg/kg per day for 7-8 days, i.p.) produced a gradual reduction in baseline synaptic transmission which was transiently reversed by WAY-100635 (0.25 mg/kg, i.p.). Ipsapirone (1 mg/kg per day for 7 days) produced a gradual and sustained reduction in the duration of vocalizations in the anxiety test which paralleled the reduction in baseline synaptic responses in the same animals. The data indicate that with repeated administration of ipsapirone, a prolongation and enhancement of the 5-HT1A receptor-mediated reduction in hippocampal excitatory synaptic transmission occurs. This delayed effect may contribute to the sustained anxiolytic and/or antidepressant effect of ipsapirone.

Animals↗

PubMed1997

Activation of group-II metabotropic glutamate receptors blocks induction of long-term potentiation and depotentiation in area CA1 of the rat in vivo.

The metabotropic glutamate receptor group-II agonist (1S,3S)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3S-ACPD; 5 microliters/10 mM, i.c.v.) prevented the induction of long-term potentiation and depotentiation in the CA1 area of the hippocampus in urethane-anaesthetised rats. These effects were prevented by the group-II metabotropic glutamate receptor antagonists alpha-methyl-(2S,3S,4S)-alpha-(carboxycyclopropyl)glycine (MCCG; 5 microliters/100 mM) and (RS)-alpha-methyl-4-tetrazolylphenylglycine (MTPG; 5 microliters/500 mM). The group-I antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA; 5 microliters/200 mM) or the group-III antagonist alpha-methyl-L-2-amino-4-phosphonobutyrate (MAP4; 5 microliters/100 mM) did not affect the block of the induction of long-term potentiation by 1S,3S-ACPD. It is concluded that activation of group-II metabotropic glutamate receptors can block both high-frequency stimulation-induced long term potentiation and low-frequency stimulation-induced depotentiation in the CA1 area in vivo.

Animals↗

PubMed1997

DCG-IV inhibits synaptic transmission by activation of NMDA receptors in area CA1 of rat hippocampus.

We investigated the synaptic depressant action of the metabotropic glutamate receptor group II agonist, (2S,1'R,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)-glycine (DCG-IV), in area CA1 of rat hippocampus. A brief bath application of DCG-IV (10 microM) caused a rapidly reversible depression to 0.57 +/- 0.22 (i.e., 43%) of baseline excitatory postsynaptic potential (epsp) slope. This depression could not be attenuated by the metabotropic glutamate receptor antagonists alpha-methyl-L-CCGI/(2S,3S,4S)-2-methyl-2-(carboxycyclopropyl++ +)glycine (MCCG), (RS)-alpha-methyl-4-tetrazolyphenylglycine (MTPG) or (S)-2-amino-2-methyl-4-phosphonobutanoic acid alpha-methyl-AP4) (MAP4). However, the DCG-IV-induced depression could be reversed by the NMDA receptor antagonist, D(-)-2-amino-5-phosphonopentanoic acid (AP5; 50 microM), and partially reversed by the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 5 microM). These results strongly suggest that DCG-IV is an agonist at NMDA receptors and provide further evidence against a role for metabotropic glutamate receptor group II in synaptic transmission in area CA1 of rat hippocampus.

2-Amino-5-phosphonovalerate↗

PubMed1997

mGluR II agonist inhibition of LTP induction, and mGluR II antagonist inhibition of LTD induction, in the dentate gyrus in vitro.

The effects of the metabotropic glutamate receptor (mGluR) group II agonist (2S,1'R,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV) and the antagonist 2S,1S',2S'-2-methyl-2-(2'-carboxycyclopropyl)glycine (MCCG) on the induction of long-term potentiation (LTP) and long-term depression (LTD) of the field excitatory postsynaptic potential (epsp) in the dentate gyrus of the rat hippocampus were investigated in vitro. In control media, high frequency stimulation (HFS) consisting of a series of trains of stimuli at 200 Hz induced LTP, and low frequency stimulation (LFS) consisting of 900 stimuli at 1 Hz induced LTD. DCG-IV (50 nM) strongly inhibited the induction of LTP. The block of LTP induction was not caused by a frequency-dependent inhibition of the epsp during HFS, as the epsps evoked during HFS were not altered by DCG-IV. MCCG (500 microM) did not inhibit the induction of LTP, but did prevent the block of LTP by DCG-IV. MCCG (500 microM) strongly inhibited the induction of LTD. DCG-IV (50 nM) did not inhibit LTD induction.

Amino Acids, Dicarboxylic↗

PubMed1997

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

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

Animals↗

PubMed1997

HFS-induced long-term potentiation and LFS-induced depotentiation in area CA1 of the hippocampus are not good models for learning.

Spatial learning in rats has been shown to be dependent on the intact hippocampus and lesioning this region impairs learning performance. Long-term potentiation (LTP) and depotentiation (DP) of synaptic transmission have been suggested to model memory formation at the neuronal level. Recently it was shown that LTP in the dentate gyrus or area CA3 of the hippocampus is not essential for the ability to learn a spatial water maze task. Here we show that the metabotropic glutamate receptor agonist (1S,3S)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3S-ACPD), which acts predominantly at presynaptic sites, only marginally impaired spatial learning in a water maze or radial arm maze (three out of eight arms baited) when injected ICV (5 microliters of a 20 mM solution). There also were small impairments in non-spatial and visual discrimination tasks, indicating that the small learning impairments were due to nonselective effects of the drug. The same dose depressed field EPSPs and completely blocked LTP induced by high-frequency stimulation (HFS, 200 Hz) in the CA1 region of the rat hippocampus in vivo. A lower (5 microliters of a 10 mM solution) dose did not depress baseline but still blocked LTP. Injecting the same dose after induction of LTP blocked DP induced by low-frequency stimulation (LFS, 10 Hz). These results indicate that neither HFS-induced LTP nor LFS-induced DP in area CA1 are good models for the induction of synaptic changes that might underlie spatial learning in the rat.

Animals↗

PubMed1997

Low-frequency stimulation induces homosynaptic depotentiation but not long-term depression of synaptic transmission in the adult anaesthetized and awake rat hippocampus in vivo.

The induction of homosynaptic long-term depression and depotentiation of previously established long-term potentiation was investigated in the CA1 hippocampal region of anaesthetized and awake adult rats following prolonged ipsilateral low-frequency stimulation of the Schaffer collateral/ commissural pathway. Prolonged low-frequency stimulation at 1-10 Hz failed to induce long-term depression of field excitatory postsynaptic potentials in the anaesthetized or awake adult rat. However, prolonged low-frequency stimulation at 5 and 10 Hz, although not at 1 or 2 Hz, did induce depotentiation of previously established long-term potentiation in anaesthetized animals. Thus, in the anaesthetized animals, 900 pulses at 10 Hz induced a depotentiation of 68%, 59% and 66% when given 10, 30 and 40 min following long-term potentiation induction. Depotentiation could also be induced at much longer times following the induction of long-term potentiation. Thus, in anaesthetized rats, depotentiation measuring 34% was induced by 10-Hz stimulation 4 h following long-term potentiation induction, and depotentiation measuring 60% was induced in two sets of experiments 24 h after long-term potentiation induction in awake animals. The results of the present study show that homosynaptic long-term depression was not induced in the adult hippocampus in vivo using stimulation protocols which are effective in hippocampal slices. However, erasure of long-term potentiation by the process of depotentiation has been shown to occur in the adult hippocampus in vivo, both at short times and at prolonged times after the induction of long-term potentiation.

Anesthesia↗

PubMed1997

Block of theta-burst-induced long-term potentiation by (1S,3S)-1-aminocyclopentane-1,3-dicarboxylic acid: further evidence against long-term potentiation as a model for learning.

It has been previously reported that block of high-frequency stimulation-induced long-term potentiation of synaptic transmission in the hippocampus does not necessarily lead to impairment of spatial learning. Here we show that (1S,3S)-1-aminocyclopentane-1,3-dicarboxylic acid, an agonist at group II metabotropic glutamate receptors, completely blocked long-term potentiation induced by a theta-burst type of stimulation protocol (five pulses at 75 Hz per train, 200 ms inter-train interval) in the CA1 region in vivo. The drug did not significantly affect synaptic responses during each train whereas inter-train facilitation of excitatory postsynaptic potentials was slightly reduced. It also produced a large reduction in paired-pulse facilitation (50 ms inter-stimulus interval), possibly indicating that an increase in inhibition might be involved in the block of long-term potentiation. The drug dose used (5 microliters of a 10 mM solution i.c.v.) was half the dose which inhibited high-frequency stimulation-induced long-term potentiation in earlier experiments but which did not prevent learning of spatial tasks. We conclude that long-term potentiation induced by a more physiological stimulation protocol which uses theta-like inter-train intervals does not appear to accurately model the synaptic changes which are believed to occur during learning either.

Action Potentials↗

PubMed1997

Evidence for involvement of the neuronal isoform of nitric oxide synthase during induction of long-term potentiation and long-term depression in the rat dentate gyrus in vitro.

The possible role of nitric oxide in the induction of long-term potentiation and long-term depression of field excitatory postsynaptic potentials in the dentate gyrus of the hippocampal slice has been investigated, in the rat, using two novel nitric oxide synthase inhibitors, 1-(2-trifluoromethylphenyl)imidazole, which is selective for the neuronal isoform in vitro, and 3-bromo-7-nitro-indazole. Long-term potentiation was induced by a series of high-frequency trains, and long-term depression was induced by prolonged low-frequency stimulation at 1 Hz. The induction of long-term potentiation was inhibited by both 1-(2-trifluoromethylphenyl)imidazole and 3-bromo-7-nitro-indazole at concentrations which did not alter the amplitude of the test excitatory postsynaptic potential. The inhibitory effect of 1-(2-trifluoromethylphenyl)imidazole on the induction of long-term potentiation was prevented by pretreatment with L-arginine, the substrate amino acid used by nitric oxide synthase for nitric oxide production. The induction of long-term depression was inhibited by both 3-bromo-7-nitro-indazole and 1-(2-trifluoromethylphenyl)imidazole at concentrations which did not affect the test excitatory postsynaptic potential. The inhibitory effect of 1-(2-trifluoromethylphenyl)imidazole was prevented by pretreatment with L-arginine. The present experiments provide strong support for the involvement of the neuronal isoform of nitric oxide synthase in the induction of long-term potentation and long-term depression.

Animals↗

PubMed1997

Induction of LTD in the dentate gyrus in vitro is NMDA receptor independent, but dependent on Ca2+ influx via low-voltage-activated Ca2+ channels and release of Ca2+ from intracellular stores.

The mechanisms of the induction of long-term depression (LTD) of field excitatory postsynaptic potentials (EPSPs) and whole cell patch-clamped excitatory postsynaptic currents (EPSCs) were studied in the dentate gyrus of the rat hippocampus. LTD of field EPSPs measuring 40% of control at 30 min poststimulation was induced by low-frequency stimulation consisting of 900 pulses at 1 Hz. LTD of EPSCs measuring 37% of control was induced by a pairing procedure consisting of 60 pulses at 1 Hz applied under voltage clamp at a holding potential of -40 mV. The induction of LTD of field EPSPs was dependent on an influx of extracellular calcium, being reduced in a low-Ca2+ (0.8 mM) medium. However, substantial LTD (26%) was still induced in such a medium, demonstrating the relatively low sensitivity of LTD induction to the level of extracellular Ca2+. A high concentration of the N-methyl-D-aspartate receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) (100 microM) did not significantly inhibit the induction of LTD of EPSCs evoked by the intracellular pairing procedure. D-AP5 partially reduced the magnitude of LTD of field EPSPs, but substantial LTD was still induced in the presence of AP5. The induction of LTD was strongly inhibited by Ni2+ (50 microM) but not by nifedipine (10 microM), indicating that Ca2+ influx via T-type, but not L-type, Ca2+ channels is required for the induction of LTD. The induction of LTD was strongly inhibited by thapsigargin, an agent known to deplete intracellular Ca2+ stores. The induction of LTD, but not long-term potentiation (LTP), was also strongly inhibited by ruthenium red, an agent known to block the ryanodine receptors located on intracellular Ca2+ stores. These results demonstrate that Ca2+ release from intracellular Ca2+ stores is required for the induction of LTD, but not LTP. The results of the present experiments suggest that the induction of LTD involves the entry of Ca2+ via low-voltage-activated voltage-gated Ca2+ channels followed by release of Ca2+ from intracellular ryanodine-receptor-sensitive Ca2+ stores.

Animals↗

PubMed1997

Conditions for the induction of long-term potentiation and long-term depression by conjunctive pairing in the dentate gyrus in vitro.

Conditions for the induction of long-term potentiation and long-term depression by conjunctive pairing in the dentate gyrus in vitro. J. Neurophysiol. 78: 2569-2573, 1997. The conditions under which long-term potentiation (LTP) and long-term depression (LTD) of excitatory postsynaptic currents were induced by the conjunctive pairing-type protocol of afferent stimulation and postsynaptic depolarization were studied in the medial perforant pathway-granule cell synapse of the dentate gyrus in vitro. The conjunctive pairing of 1-Hz afferent stimulation and steady state postsynaptic depolarization to 0 mV did not induce LTP or LTD. Inhibition of LTD induction with a phosphatase inhibitor or ruthenium red resulted in induction of LTP after the conjunctive pairing. Such LTP induction was N-methyl--aspartate dependent. Conversely, inhibition of LTP induction with a kinase inhibitor resulted in LTD induction after the conjunctive pairing. Thus the failure to induce LTP or LTD with the pairing protocol involving depolarization to 0 mV membrane potential was due to simultaneous activation of intracellular processes that generate the induction of LTP and LTD. Increasing the frequency of afferent stimulation to 200 Hz, even for just eight stimuli, resulted in LTP induction. The studies show that two factors govern the induction of LTP/LTD, membrane potential and frequency of afferent stimulation, with either increased depolarization or increased afferent stimulation favoring LTP induction.

2-Amino-5-phosphonovalerate↗

PubMed1997

LTP induction dependent on activation of Ni2+-sensitive voltage-gated calcium channels, but not NMDA receptors, in the rat dentate gyrus in vitro.

LTP induction dependent on activation of Ni2+-sensitive voltage-gated calcium channels, but not NMDA receptors, in the rat dentate gyrus in vitro. J. Neurophysiol. 78: 2574-2581, 1997. A N-methyl--aspartate receptor (NMDAR)-independent long-term potentiation (LTP) has been investigated in the dentate gyrus of the hippocampus in vitro in the presence of the NMDAR antagonist, -2-amino-phosphonopentanoate (50-100 mu M), at a concentration that completely blocked NMDAR-mediated excitatory postsynaptic currents (EPSCs). LTP of patch-clamped EPSCs was induced by pairing low-frequency evoked EPSCs (1 Hz) with depolarizing voltage pulses designed to predominately open low-voltage-activated (LVA) Ca2+ channels. Voltage pulses alone induced only a short-term potentiation. The LTP was blocked by intracellular application of the rapid Ca2+ chelator bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid, demonstrating that a rise in intracellular Ca2+ is required for the NMDAR-independent LTP induction. The NMDAR-independent LTP induction also was blocked by Ni2+ at a low extracellular concentration (50 mu M), which is known to strongly block LVA Ca2+ channels. However, Ni2+ did not inhibit the NMDAR-dependent LTP induced by high-frequency stimulation (HFS). The NMDAR-independent LTP induction was not blocked by high concentrations of the L-type Ca2+ channel blocker nifedipine (10 mu M). The NMDAR-independent LTP was inhibited by the metabotropic glutamate receptor ligand (+)-alpha-methyl-4-carboxyphenylglycine. These experiments demonstrate the presence of a NMDAR-independent LTP induced by Ca2+ influx via Ni2+-sensitive, nifedipine-insensitive voltage-gated Ca2+ channels, probably LVA Ca2+ channels. Induction of the NMDAR-independent LTP was inhibited by prior induction of HFS-induced NMDAR-dependent LTP, demonstrating that although the NMDAR-dependent and NMDAR-independent LTP use a different Ca2+ channel for Ca2+ influx, they share a common intracellular pathway.

2-Amino-5-phosphonovalerate↗