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G L Collingridge

Publications and source records attributed to G L Collingridge.

At least 37 records · Page 2Linked to original sources
PubMed2000

PDZ proteins interacting with C-terminal GluR2/3 are involved in a PKC-dependent regulation of AMPA receptors at hippocampal synapses.

We investigated the role of PDZ proteins (GRIP, ABP, and PICK1) interacting with the C-terminal GluR2 by infusing a ct-GluR2 peptide ("pep2-SVKI") into CA1 pyramidal neurons in hippocampal slices using whole-cell recordings. Pep2-SVKI, but not a control or PICK1 selective peptide, caused AMPAR-mediated EPSC amplitude to increase in approximately one-third of control neurons and in most neurons following the prior induction of LTD. Pep2-SVKI also blocked LTD; however, this occurred in all neurons. A PKC inhibitor prevented these effects of pep2-SVKI on synaptic transmission and LTD. We propose a model in which the maintenance of LTD involves the binding of AMPARs to PDZ proteins to prevent their reinsertion. We also present evidence that PKC regulates AMPAR reinsertion during dedepression.

Adaptor Proteins, Signal Transducing↗
PubMed2000

A novel, competitive mGlu(5) receptor antagonist (LY344545) blocks DHPG-induced potentiation of NMDA responses but not the induction of LTP in rat hippocampal slices.

1. We have investigated the pharmacological properties of LY344545, a structurally related epimer of the broad spectrum competitive metabotropic glutamate receptor antagonist, LY341495. We have found that LY344545 also antagonizes competitively nearly all mGlu receptor subtypes, but with a wide spectrum of activity. The order of potency for the human receptor isoforms was mGlu(5a) (IC(50) of 5. 5+/-0.6 microM)>mGlu(2)=mGlu(3)>mGlu(1alpha)=mG lu(7)>mGlu(6)=mGlu(8). No significant mGlu(4) receptor antagonist activity was detected at the highest concentration used (100 microM). 100 microM LY344545 displaced 50+/-5% of [(3)H]-CGP39653 binding, but less than 30% of [(3)H]-kainate or [(3)H]-AMPA in radioligand binding assays. 2. LY344545 antagonized L-glutamate stimulated Ca(2+) release in CHO cells transfected with mGlu receptors in a concentration dependent manner with a 10 fold higher affinity for the rat mGlu(5a) receptor (K:(i)=2.1+/-0.6 microM) compared to the rat mGlu(1alpha) receptor (K:(i)=20.5+/-2.1 microM). 50 microM (1S, 3R)-ACPD-induced Ca(2+) rises in hippocampal CA1 neurones were also antagonized (IC(50)=6. 8+/-0.7 microM). 3. LY344545 antagonized 10 microM (S)-3,5-DHPG-induced potentiation of NMDA depolarizations in CA1 neurones (EC(50)=10. 6+/-1.0 microM). At higher concentrations (> or =100 microM), LY344545 was an NMDA receptor antagonist. 4. LY344545 also blocked the induction, but not the expression, of LTP at CA3 to CA1 synapses with an IC(50)>300 microM. This effect is consistent with its weak activity at NMDA receptors. 5. These results demonstrate that the binding of ligands to mGlu receptor subtypes is critically dependent on the spatial orientation of the same molecular substituents within a given chemical pharmacophore. The identification of LY344545 as the first competitive antagonist to show selectivity towards mGlu(5) receptors supports the potential to design more selective and potent competitive antagonists of this receptor. 6. These results further indicate that mGlu receptor-mediated potentiation of NMDA responses is not essential for the induction of LTP.

Amino Acids↗
PubMed2000

Modulation of synaptic transmission in the rat ventral septal area by the pharmacological activation of metabotropic glutamate receptors.

The ventral septal area (VSA) is considered to be critically involved in the control of the height and duration of fever. The major excitatory input to this region of the brain is glutamatergic, and the aim of this study was to investigate possible modulation of this synapse by metabotropic glutamate (mGlu) receptors. Whole-cell patch recordings were made from individual VSA neurons voltage-clamped at -60 mV. Activation of either group I or group II mGlu receptors (by bath application of 3,5-dihydroxyphenylglycine (DHPG) or (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV), respectively) produced a long-lasting depression of synaptic transmission which in both cases was insensitive to the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5). In contrast, application of (S)-2-amino-4-phosphonobutyric acid (L-AP4), a group III mGlu receptor agonist, had a biphasic effect on synaptic transmission in the VSA, first eliciting a transient depression of transmission during drug application, followed by a marked and sustained potentiation of synaptic transmission upon drug washout. The response elicited by L-AP4 was dependent on NMDA receptor activation, as in the presence of D-AP5 the potentiation was replaced by an underlying long-term depression (LTD) of transmission. These data provide the first evidence that metabotropic glutamate receptor agonists can induce both NMDA receptor-dependent and -independent modulation of synaptic transmission in the VSA.

2-Amino-5-phosphonovalerate↗
PubMed2000

A role for protein kinase C in a form of metaplasticity that regulates the induction of long-term potentiation at CA1 synapses of the adult rat hippocampus.

The possibility that protein kinase C (PKC) is involved in the induction of N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) at CA1 synapses in the hippocampus has been the subject of considerable investigation. However, many of the conclusions have been drawn from the use of relatively nonspecific PKC inhibitors. In the present study we have examined the role of PKC in tetanus-induced LTP of AMPA receptor-mediated synaptic transmission in hippocampal slices obtained from adult rats. In particular, we have investigated the possible role of PKC in a molecular switch process that is triggered by the synaptic activation of metabotropic glutamate receptors and regulates the induction of LTP. We find that the three PKC inhibitors examined, chelerythrine, Ro-31-8220 and Gö 6983, all block the setting of the molecular switch at concentrations consistent with inhibition of PKC. In contrast, these inhibitors are without affect on the induction of LTP, even when applied in very much higher concentrations. A PKA inhibitor, Rp-cAMPS, had no effect on either process. We suggest that neither PKC nor PKA is required to induce LTP at this synapse. However, PKC is involved in the regulation of LTP induction, via the molecular switch process.

Alkaloids↗
PubMed1999

Kainate receptors are involved in synaptic plasticity.

The ability of synapses to modify their synaptic strength in response to activity is a fundamental property of the nervous system and may be an essential component of learning and memory. There are three classes of ionotropic glutamate receptor, namely NMDA (N-methyl-D-aspartate), AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid) and kainate receptors; critical roles in synaptic plasticity have been identified for two of these. Thus, at many synapses in the brain, transient activation of NMDA receptors leads to a persistent modification in the strength of synaptic transmission mediated by AMPA receptors. Here, to determine whether kainate receptors are involved in synaptic plasticity, we have used a new antagonist, LY382884 ((3S, 4aR, 6S, 8aR)-6-((4-carboxyphenyl)methyl-1,2,3,4,4a,5,6,7,8,8a-decahydro isoquinoline-3-carboxylic acid), which antagonizes kainate receptors at concentrations that do not affect AMPA or NMDA receptors. We find that LY382884 is a selective antagonist at neuronal kainate receptors containing the GluR5 subunit. It has no effect on long-term potentiation (LTP) that is dependent on NMDA receptors but prevents the induction of mossy fibre LTP, which is independent of NMDA receptors. Thus, kainate receptors can act as the induction trigger for long-term changes in synaptic transmission.

Animals↗
PubMed1999

Rapid internalization and surface expression of a functional, fluorescently tagged G-protein-coupled glutamate receptor.

l-Glutamate is the principal excitatory neurotransmitter in the vertebrate central nervous system, where it mediates many of its actions via G-protein-coupled metabotropic glutamate (mGlu) receptors. Since little is known about the dynamics of mGlu receptors at the plasma membrane, we have constructed a fusion protein comprising the mGlu receptor subtype 1alpha (mGlu1alpha) and green fluorescent protein (GFP). Using imaging of Ca2+ release from intracellular stores as a functional assay, the agonist pharmacology of this fluorescently tagged receptor was found to be similar to that of the wild-type receptor when expressed in HEK-293 cells. Receptor movement and function were measured simultaneously by combined imaging of Ca2+, using fura-red, and GFP fluorescence in single cells. Exposure to agonist induced a rapid loss of up to 30% of membrane-associated fluorescence, with a corresponding decrease in the functional response. Following removal of the agonist there was recovery of both the membrane fluorescence and the functional response. These data suggest that the surface expression of G-protein-coupled glutamate receptors might be rapidly regulated in response to agonist activation.

Biological Transport↗
PubMed1999

Expression of early hippocampal CA1 LTP does not lead to changes in AMPA-EPSC kinetics or sensitivity to cyclothiazide.

We have analysed whether the expression of long-term potentiation (LTP) in rat hippocampal CA1 neurons involves a change in the kinetics of (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated excitatory postsynaptic currents (EPSCs) (AMPA-EPSCs) or their susceptibility to the AMPA receptor modulator cyclothiazide. AMPA-EPSCs in the CA1 region were evoked by alternate stimulation of two independent Schaffer collateral-commissural inputs of slices of adult rat hippocampus. In the current-clamp mode a strong tetanus (100 Hz, 1 s) applied to one input (input I) induced stable LTP of AMPA-EPSCs in this input, while the control input (input II) remained unaffected. For neither input were EPSC rise time and decay kinetics significantly changed. The application of cyclothiazide prolonged the rise time and the decay time constants of the AMPA-EPSCs in both control and potentiated inputs to the same extent (Input I-rise time: 198+/-8%, decay: 148+/-12%; input II-rise time: 212+/-14%, decay: 144+/-19%; n=8). Furthermore, when present during tetanization cyclothiazide did not occlude LTP, suggesting that cyclothiazide and tetanic stimulation enhance AMPA-EPSCs via independent mechanisms. Our findings argue against changes in (de-)activation or desensitization of AMPA receptors as the molecular basis for the expression of LTP.

Animals↗
PubMed1999

Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein.

Abnormal processing of amyloid precursor protein (APP), in particular the generation of beta-amyloid (Abeta) peptides, has been implicated in the pathogenesis of Alzheimer's disease. This study examined the consequences of deleting the APP gene on hippocampal synaptic plasticity, and upon the biophysical properties of morphologically identified neurones in APP-null mice. The hippocampus of APP-null mice had a characteristic increase in gliosis throughout the CA1 region and a disruption of staining for the dendritic marker MAP2 and the presynaptic marker synaptophysin. The disruption of MAP2 staining was associated with a significant reduction in overall dendritic length and projection depth of biocytin labeled CA1 neurones. In two groups of APP-null mice that were examined at 8-12 months, and 20-24 months of age, there was an impairment in the formation of long-term potentiation (LTP) in the CA1 region compared to isogenic age matched controls. This LTP deficit was not associated with an alteration in the amplitude of EPSPs at low stimulus frequencies (0.033 Hz) or facilitation during a 100 Hz stimulus train, but was associated with a reduction in post-tetanic potentiation. Paired-pulse depression of GABA-mediated inhibitory post-synaptic currents was also attenuated in APP-null mice. These data demonstrate that the impaired synaptic plasticity in APP deficient mice is associated with abnormal neuronal morphology and synaptic function within the hippocampus.

Aging↗
PubMed1999

A CaMKII inhibitor, KN-62, facilitates DHPG-induced LTD in the CA1 region of the hippocampus.

We have shown previously that activation of mGlu receptors using a group I specific mGlu receptor agonist, (R,S)-3,5-dihydroxyphenylglycine (DHPG), can induce long-term depression (LTD) in the CA1 region of the hippocampus (Palmer et al., 1997). We now report that DHPG-induced LTD is facilitated by treatment with KN-62, an inhibitor of certain Ca2+/calmodulin-dependent protein kinases (CaMKs), including CaMKII.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1999

An investigation into signal transduction mechanisms involved in DHPG-induced LTD in the CA1 region of the hippocampus.

Previously, we have found that activation of mGlu receptors using a group I-specific mGlu receptor agonist, (RS)-3,5-DHPG, can induce long-term depression (LTD) in the CA1 region of the hippocampus and that, once established, this synaptic depression can be reversed by application of the mGlu receptor antagonist, (S)-MCPG [Palmer et al., 1997. Neuropharmacology 36, 1517-1532]. We have started to investigate the signal transduction mechanisms involved in these effects. Group I mGlu receptors couple to phospholipase C and therefore can activate protein kinase C and mobilise Ca2+ from intracellular stores. However, neither protein kinase C inhibitors (chelerythrine or Ro 31-8220) nor agents which deplete intracellular Ca2+ stores (thapsigargin or cyclopiazonic acid) were able to prevent DHPG-induced LTD. Furthermore, the ability of MCPG to reverse DHPG-induced LTD was not prevented by these compounds. These results suggest that it is unlikely that DHPG-induced LTD, or its reversal by MCPG, is produced via activation of either protein kinase C or by release of Ca2+ from intracellular stores.

Alkaloids↗
PubMed1999

DHPG-induced LTD in area CA1 of juvenile rat hippocampus; characterisation and sensitivity to novel mGlu receptor antagonists.

We have used extracellular microelectrode recording to characterise a form of long-term depression (LTD) of synaptic transmission that can be induced by metabotropic glutamate (mGlu) receptor activation in the CA1 region of the young (12-18 day old) rat hippocampus. Activation of group I mGlu receptors by the specific agonist 3,5-dihydroxyphenylglyine (DHPG) induced LTD of field excitatory postsynaptic potentials (fEPSPs). The mGlu5 selective agonist 2-chloro-5-hydroxyphenylglycine was also capable of inducing LTD. In contrast, the group II specific agonist DCG-IV had no effect on synaptic transmission, whilst the group III receptor agonist (S)-2-amino-4-phosphonobutyrate elicited a depression that reversed fully upon agonist washout. DHPG-induced LTD could still be generated after prior saturation of electrically-induced NMDA receptor-dependent LTD. DHPG-induced LTD was reversed by tetanic stimulation comprising 100 shocks delivered at 100 Hz. A novel mGlu receptor antagonist, (RS)-2-amino-2-(3-cis and trans-carboxycyclobutyl-3-(9-thioxanthyl)propionic acid) (LY393053) that potently inhibits mGlu1 and mGlu5 receptors, prevented the induction of DHPG-induced LTD. Like other mGlu receptor antagonists, LY393053 also reversed pre-established DHPG-induced LTD. In contrast, a potent mGlu1 selective antagonist (S)-2-methyl-4-carboxyphenylglycine (LY367385) did not prevent the induction of DHPG-induced LTD. In conclusion, DHPG, probably via activation of mGlu5 receptors, is able to induce a robust form of LTD in the CA1 region of the young rat hippocampus that is mechanistically distinct from NMDA receptor-dependent homosynaptic LTD.

Animals↗
PubMed1999

Regulation of depolarizing GABA(A) receptor-mediated synaptic potentials by synaptic activation of GABA(B) autoreceptors in the rat hippocampus.

The role of GABA(B) autoreceptors in the regulation of GABA(A) and GABA(B) receptor-mediated inhibitory post-synaptic potentials (IPSPs) during repetitive synaptic activation has been established. In the present study the role of these receptors in the regulation of depolarising GABA(A) receptor-mediated synaptic potentials (DPSP(A)s) in the CA1 region of the hippocampus is documented. Following blockade of AMPA and NMDA receptor-mediated synaptic excitation, DPSP(A)s could be evoked by a single stimulus. The size of this response was enhanced by increasing the stimulus number (1-10 shocks) or stimulus frequency (10-100 Hz). Conversely, the amplitude of the DPSP(A) was dramatically reduced by a priming pulse (single shock) or priming burst (four shocks) delivered 200 ms beforehand. This activity-dependent depression was eliminated by the GABA(B) receptor antagonist CGP 35348 (1 mM). As such, GABA(B) autoreceptor-mediated regulation of DPSP(A)s prevented a pronounced, potentially epileptogenic, DPSP(A) from occurring during theta burst stimulation. Thus, during repetitive stimulation, activation of GABA(B) autoreceptors not only enables a transient reduction in GABA(A) receptor-mediated synaptic inhibition sufficient to enable NMDA receptor-dependent synaptic plasticity [Davies, C.H., Collingridge, G.L., 1996. J. Physiol. 496.2, 451-470] but also prevents the development of a potentially pathogenic depolarising GABA-mediated synaptic potential.

Animals↗
PubMed1999

Synaptic depression induced by pharmacological activation of metabotropic glutamate receptors in the perirhinal cortex in vitro.

The perirhinal cortex is crucially involved in various forms of learning and memory. Decrements in neuronal responsiveness occur in the perirhinal cortex with stimulus repetition during visual recognition performance. However, very little is known concerning the underlying mechanisms of synaptic transmission and plasticity in this cortical region. In this study, we provide evidence demonstrating the presence of functional group I, II and III metabotropic glutamate receptors in the rat perirhinal cortex in vitro. Furthermore, the results demonstrate long-lasting synaptic depression in the perirhinal cortex. Extracellular synaptic responses were recorded from superficial layers of the perirhinal cortex directly below the rhinal sulcus, in response to electrical stimuli delivered in the superficial or intermediate layers to the entorhinal or temporal cortex sides of the rhinal sulcus. Evoked synaptic potentials were depressed during bath perfusion of each of the following: the broad-spectrum metabotropic glutamate receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid, the selective group I agonist (R,S)-3,5-dihydroxyphenylglycine, the group II agonist (2S,1'R,2'R,3'R)-(2',3'-dicarboxycyclopropyl)glycine and the group III agonist (S)-2-amino-4-phosphonobutanoate. Furthermore, there was a long-lasting depression of synaptic transmission following washout of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid, (R,S)-3,5-dihydroxyphenylglycine or (2S,1'R,2'R,3'R)-(2',3'-dicarboxy-cyclopropyl)glycine. Activation of group III metabotropic glutamate receptors by (S)-2-amino-4-phosphonobutanoate did not result in long-lasting changes in synaptic transmission. Thus, the pharmacological activation of metabotropic glutamate receptors can produce short- or long-term changes in synaptic transmission in the perirhinal cortex. It is possible therefore, that metabotropic glutamate receptors are involved in the decrement in neuronal responsiveness associated with visual recognition in the perirhinal cortex.

Animals↗
PubMed1999

Surface expression of AMPA receptors in hippocampal neurons is regulated by an NSF-dependent mechanism.

Here, we show that disruption of N-ethylmaleimide-sensitive fusion protein- (NSF-) GluR2 interaction by infusion into cultured hippocampal neurons of a blocking peptide (pep2m) caused a rapid decrease in the frequency but no change in the amplitude of AMPA receptor-mediated miniature excitatory postsynaptic currents (mEPSCs). N-methyl-D-aspartate (NMDA) receptor-mediated mEPSCs were not changed. Viral expression of pep2m reduced the surface expression of alpha-amino-3-hydroxy-5-methyl-isoxazolepropionate (AMPA) receptors, whereas NMDA receptor surface expression in the same living cells was unchanged. In permeabilized neurons, the total amount of GluR2 immunoreactivity was unchanged, and a punctate distribution of GluR2 was observed throughout the dendritic tree. These data suggest that the NSF-GluR2 interaction is required for the surface expression of GluR2-containing AMPA receptors and that disruption of the interaction leads to the functional elimination of AMPA receptors at synapses.

Adenoviridae↗
PubMed1999

Hippocampal LTD expression involves a pool of AMPARs regulated by the NSF-GluR2 interaction.

We investigated whether the interaction between the N-ethyl-maleimide-sensitive fusion protein (NSF) and the AMPA receptor (AMPAR) subunit GluR2 is involved in synaptic plasticity in the CA1 region of the hippocampus. Blockade of the NSF-GluR2 interaction by a specific peptide (pep2m) introduced into neurons prevented homosynaptic, de novo long-term depression (LTD). Moreover, saturation of LTD prevented the pep2m-induced reduction in AMPAR-mediated excitatory postsynaptic currents (EPSCs). Minimal stimulation experiments indicated that both pep2m action and LTD were due to changes in quantal size and quantal content but were not associated with changes in AMPAR single-channel conductance or EPSC kinetics. These results suggest that there is a pool of AMPARs dependent on the NSF-GluR2 interaction and that LTD expression involves the removal of these receptors from synapses.

Animals↗
PubMed1999

Roles of metabotropic glutamate receptors in LTP and LTD in the hippocampus.

Metabotropic L-glutamate receptors are involved in various forms of synaptic plasticity in the hippocampus. The use of a new antagonist (LY341495) that blocks all known metabotropic L-glutamate receptors in the brain, together with subtype-selective antagonists, has identified multiple roles both for cloned and novel metabotropic L-glutamate receptors in hippocampal long-term potentiation and long-term depression.

Animals↗
PubMed1999

Antagonist activity of alpha-substituted 4-carboxyphenylglycine analogues at group I metabotropic glutamate receptors expressed in CHO cells.

1. We have investigated the antagonist properties of 6 alpha-substituted phenylglycine analogues based on the structure of 4-carboxyphenylglycine (4-CPG) for group I metabotropic glutamate receptors (mGlu1alpha and mGlu5a) permanently expressed in CHO cells. 2. (S)-4-CPG and (S)-MCPG were the most selective mGlu1alpha receptor antagonists. Longer chain alpha-carbon substitutions resulted in a progressive loss of antagonist affinity at mGlu1alpha receptors but not at mGlu5a receptors. Thus mGlu1alpha receptor antagonists require small aliphatic groups at the alpha-position. Alpha-cyclopropyl-4-CPG showed a tendency towards mGlu5a selectivity, suggesting that bulky groups at this position may favour mGlu5a receptor antagonism. 3. We demonstrate that the mGlu5a receptor displays agonist-dependent antagonism. L-glutamate-induced Ca2+ release in mGlu5a receptor expressing cells was more susceptible to antagonism by cyclic alpha-carbon derivatives than (S)-3,5-dihydroxyphenylglycine (DHPG)-induced Ca2+ release in the same cell line. 4. The data presented suggests that mGlu1alpha and mGlu5a receptors have different steric and/or conformational requirements for the binding of antagonists and different amino acids which could interact with agonists. 5. These phenylglycine analogues could provide leads for the development of subtype selective antagonists.

Animals↗