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G L Collingridge

Publications and source records attributed to G L Collingridge.

At least 109 records · Page 6Linked to original sources
PubMed1992

L-glutamate and acetylcholine mobilise Ca2+ from the same intracellular pool in cerebellar granule cells using transduction mechanisms with different Ca2+ sensitivities.

Ca2+ mobilisation induced by L-glutamate (Glu) and acetylcholine (ACh) has been studied in cultured cerebellar granule cells using digital fluorescence microscopy. The ability of Glu-receptor activation to mobilise Ca2+ was decreased when [Ca2+]o was lowered to 10 microM (from 1.8 mM). It was enhanced when [Ca2+]i was raised using 25 mM external K+ or by N-methyl-D-aspartate (NMDA), which selectively activates a distinct Glu-receptor subtype. The enhancement was dependent on entry of external Ca2+. In contrast, the ability of ACh receptor activation to mobilise Ca2+ was not affected by these conditions. Furthermore, pretreatment with pertussis toxin inhibited Ca2+ mobilisation in response to Glu-receptor activation without affecting mobilisation in response to ACh. However, activation of both receptors mobilised Ca2+ from a common, thapsigargin-sensitive pool. We conclude that there are differences in the Ca2+ mobilization pathways for the two receptor systems in cerebellar granule cells. The Ca(2+)-sensitivity of this Ca2+ mobilizing Glu receptor may have implications for its function in neuronal synaptogenesis and plasticity.

Acetylcholine↗
PubMed1992

Interactions between Ca2+ mobilizing mechanisms in cultured rat cerebellar granule cells.

1. The interactions between IP3 receptor-mediated and Ca(2+)-induced Ca2+ release were investigated in cerebellar granule cell bodies, using the techniques of microfluorimetry and image analysis. 2. The IP3-sensitive Ca2+ release mechanism was activated using acetylcholine (ACh) and the selective metabotropic glutamate receptor agonist 1-aminocyclopentane-1S,3R-dicarboxylic acid (ACPD). Caffeine was used to activate, and ryanodine to inhibit, the Ca(2+)-induced Ca2+ release process. Thapsigargin was used to deplete intracellular Ca2+ stores. 3. Transient applications of caffeine (5-50 mM), ACPD (50-500 microM) and ACh (0.05-1 microM) mobilized intracellular Ca2+ ([Ca2+]i). Ca2+ mobilizing responses to 50 mM caffeine and 1 microM ACh increased with time in culture until day 4. However, beyond this period the responsiveness of cells to caffeine, but not to ACh, declined markedly. 4. Responses induced by ACPD and ACh were inhibited in the presence of caffeine at concentrations below those which mobilized Ca2+ (1-5 mM). This effect was not due to Ca2+ pool depletion, elevation of cAMP or inhibition of phosphodiesterases. 5. Prior challenge with ACh or ACPD inhibited Ca2+ mobilization induced by caffeine (50 mM). Transient exposure to caffeine inhibited subsequent responses to ACh through a mechanism which involved store depletion. 6. Thapsigargin (0.1-1 microM) inhibited, to a similar extent, Ca2+ mobilization induced by caffeine, ACPD and ACh. 7. Ryanodine (10 microM) antagonized Ca2+ mobilization induced by caffeine, ACh and ACPD. However, the ability of ryanodine to block inositol 1,4,5-trisphosphate-linked agonist responses varied considerably between cells. The sensitivity of ACh-induced responses to ryanodine correlated with the sensitivity of the cells to caffeine. 8. The possible explanations for the pronounced interactions between IP3 receptor-mediated and Ca(2+)-induced Ca2+ release processes in cerebellar granule cells are discussed.

Acetylcholine↗
PubMed1991

GABA autoreceptors regulate the induction of LTP.

Understanding the mechanisms involved in long-term potentiation (LTP) should provide insights into the cellular and molecular basis of learning and memory in vertebrates. It has been established that in the CA1 region of the hippocampus the induction of LTP requires the transient activation of the N-methyl-D-aspartate (NMDA) receptor system. During low-frequency transmission, significant activation of this system is prevented by gamma-aminobutyric acid (GABA) mediated synaptic inhibition which hyperpolarizes neurons into a region where NMDA receptor-operated channels are substantially blocked by Mg2+ (refs. 5, 6). But during high-frequency transmission, mechanisms are evoked that provide sufficient depolarization of the postsynaptic membrane to reduce this block and thereby permit the induction of LTP. We now report that this critical depolarization is enabled because during high-frequency transmission GABA depresses its own release by an action on GABAB autoreceptors, which permits sufficient NMDA receptor activation for the induction of LTP. These findings demonstrate a role for GABAB receptors in synaptic plasticity.

2-Chloroadenosine↗
PubMed1991

Long-term potentiation of NMDA receptor-mediated synaptic transmission in the hippocampus.

Neurotransmission at most excitatory synapses in the brain operates through two types of glutamate receptor termed alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors; these mediate the fast and slow components of excitatory postsynaptic potentials respectively. Activation of NMDA receptors can also lead to a long-lasting modification in synaptic efficiency at glutamatergic synapses; this is exemplified in the CA1 region of the hippocampus, where NMDA receptors mediate the induction of long-term potentiation (LTP). It is believed that in this region LTP is maintained by a specific increase in the AMPA receptor-mediated component of synaptic transmission. We now report, however, that a pharmacologically isolated NMDA receptor-mediated synaptic response can undergo robust, synapse-specific LTP. This finding has implications for neuropathologies such as epilepsy and neurodegeneration, in which excessive NMDA receptor activation has been implicated. It adds fundamentally to theories of synaptic plasticity because NMDA receptor activation may, in addition to causing increased synaptic efficiency, directly alter the plasticity of synapses.

Animals↗
PubMed1991

Ammonium ions mobilize calcium from an internal pool which is insensitive to TRH and ionomycin in bovine anterior pituitary cells.

The effects of NH4Cl on cytoplasmic free calcium concentration ([Ca2+]i) and pH (pHi) in single bovine anterior pituitary cells were determined using fluorescence imaging microscopy. Addition of NH4Cl (10-40 mM) in the presence of 1 mM extracellular calcium ([Ca2+]e) increased [Ca2+]i to a peak which then fell to a sustained plateau, returning to resting levels upon removal of NH4Cl. In medium containing 0.1 microM [Ca2+]e, or in 1 mM [Ca2+]e medium containing 0.1 microM nitrendipine, the plateau was absent leaving only a transient [Ca2+]i spike. NH4Cl also increased pHi and this, like the [Ca2+]i plateau, remained elevated during the continued presence of NH4Cl. In medium containing only 0.1 microM [Ca2+]e, to preclude refilling of internal stores by entry of external calcium, repeated exposures to NH4Cl induced repeated [Ca2+]i transients. In contrast, only the initial exposure to thyrotropin releasing hormone (TRH; 20-500 nM) caused a [Ca2+]i rise but, after an additional exposure to NH4CI, TRH responses re-emerged in some cells. Pre-treatment with the calcium ionophore ionomycin abolished the rise caused by TRH, but neither TRH nor ionomycin pretreatment affected the response to NH4Cl. Neither acetate removal nor methylamine increased [Ca2+]i in medium containing 0.1 microM [Ca2+]e, although in both cases pHi increased. We conclude that in bovine anterior pituitary cells NH4Cl raises [Ca2+]i by two independent pathways, increasing net calcium entry and mobilizing Ca2+ from a TRH-insensitive calcium store.

Ammonium Chloride↗
PubMed1991

Electrogenic uptake contributes a major component of the depolarizing action of L-glutamate in rat hippocampal slices.

1. A grease-gap technique has been used to measure d.c. potentials, in response to the application of excitatory amino acids and electrical stimulation of the Schaffer collateral-commissural pathway, in the CA1 region of rat hippocampal slices. The actions of L-glutamate (L-Glu) have been quantified and compared to those of structurally related compounds. 2. Perfusion of L-Glu (90s applications) depolarized the tissue with a threshold of approximately 50 microM and a maximum response in excess of 10 mM. L-Aspartate (L-Asp) produced a similar dose-response relationship. By comparison N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) were more potent excitants, producing dose-dependent depolarizations over the range 2-50 microM. 3. Application of the agonists depressed the amplitude of electrically-evoked synaptic responses; an effect that presumably reflects depolarization of neuronal tissue. However, for a given agonist-induced d.c. potential. L-Glu or L-Asp caused smaller depressions of synaptic responses than did either NMDA or AMPA. 4. The combined application of 50 microM D-2-amino-5-phosphonopentanoate (AP5) and 10 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) substantially depressed synaptic responses and antagonized responses to NMDA and AMPA producing mean (+/- s.e.) dose-ratios of 12.2 +/- 1.2 and 7.0 +/- 0.8, respectively. However, these compounds produced minimal antagonism of responses to L-Glu and L-Asp (dose-ratios of 1.5 +/- 0.1 and 1.5 +/- 0.2, respectively). 5. Responses to the stereoisomers of homocysteate (HCA) were compared over the range 50 microM to 10 mM. D-HCA was approximately 3.6 times more potent than L-HCA and was antagonized to a greater extent by the combined application of 50 microM AP5 and 10 microM CNQX; the dose ratios were 8.7 + 0.8 and 5.1 + 0.9 for the D- and L- isomers, respectively. 6. The application of high doses of an excitant (e.g., 50mM L-Glu or 5mM D-HCA) caused an irreversible loss of sensitivity to NMDA and AMPA and abolished synaptic transmission. Responses to the other excitants were depressed by this excitotoxic lesion in the following order: D-HCA > L-HCA > L-Glu = LAsp. In slices treated in this manner, L-Glu, L-Asp and L-HCA produced very similar dose-response curves. 7. Some slices were unresponsive to NMDA, AMPA and electrical stimulation from the onset of the experiment but had sensitivity to L-Glu, L-Asp and L-HCA similar to that of slices that had received an excitotoxic lesion. 8. Slices that were experimentally lesioned, such that they became unresponsive to synaptic stimulation, AMPA and NMDA, were depolarized by a variety of compounds when tested at 5 mm. The D- and L- enantiomers of Asp and Glu produced similar responses and were slightly more active than quisqualate and threo-hydroxy-L-aspartate (THLA). Glycine, L-serine, D-serine, L-alanine and 4-aminobutanoate (GABA) elicited responses 15-30% of the size, while L-lysine, alpha-amino-isobutanoate and L-proline produced depolarizations of less than 10% of the size of those induced by 5mM L-Glu. NMDA and dihydrokainate were either inactive or induced small negative shifts in the d.c. potential. 9. We conclude that when hippocampal slices are perfused with L-Glu (or L-Asp) the main source of the depolarization is due to an interaction with an electrogenic carrier system.

2-Amino-5-phosphonovalerate↗
PubMed1991

Involvement of excitatory amino acid receptors in long-term potentiation in the Schaffer collateral-commissural pathway of rat hippocampal slices.

The present article reviews studies from our laboratory, which have shown that excitatory amino acids receptors of the N-methyl-D-aspartate type are involved in the induction of long-term potentiation in the Schaffer collateral-commissural pathway of rat hippocampal slices. The nature of the excitatory amino acid receptors that mediate the response that is modified by the induction of long-term potentiation is also considered. The mechanism of induction of long-term potentiation is discussed, as are some possible stages that are required for the maintenance of this process. Some new data are presented concerning the ability of N-methyl-D-aspartate to potentiate synaptic transmission and to depress the amplitude of the presynaptic fibre volley. Concerning the potentiation, it is shown that brief (1-2 min) perfusion of slices with N-methyl-D-aspartate is sufficient to potentiate synaptic transmission for at least 3 h. The N-methyl-D-aspartate induced depression of the presynaptic fibre volley is shown to be transient and independent of synaptic transmission.

Animals↗
PubMed1990

Whole-cell patch-clamp recordings of an NMDA receptor-mediated synaptic current in rat hippocampal slices.

Whole-cell patch-clamp recordings and pharmacological techniques have been used to obtain low noise recordings of 2 excitatory postsynaptic synaptic currents (termed EPSCA and EPSCB) evoked by stimulation of the Schaffer collateral-commissural pathway in rat hippocampal slices. EPSCA was blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and EPSCB was blocked by D-2-amino-5-phosphonovalerate (APV), indicating their mediation by non-N-methyl-D-aspartate (non-NMDA) and NMDA receptors, respectively. EPSCB has a slower time-course than EPSCA and its current-voltage relationship was highly non-linear with a region of negative slope conductance from -35 to -100 mV. These properties of EPSCA and EPSCB can explain their differing participation in synaptic transmission in this pathway.

2-Amino-5-phosphonovalerate↗
PubMed1990

Activation of the glycine site in the NMDA receptor is necessary for the induction of LTP.

The effects of 7-chlorokynurenate (7-C1KY) were examined on N-methyl-D-aspartate (NMDA) receptor-mediated synaptic mechanisms in the CA1 region of rat hippocampal slices. 7-C1KY depressed both the NMDA receptor-mediated component of synaptic transmission recorded in Mg2(+)-free medium and the induction of long-term potentiation (LTP) in Mg2(+)-containing medium. Both of these effects were reversed by D-serine, suggesting that the action of 7-C1KY was at the allosteric glycine site on the NMDA receptor.

Action Potentials↗
PubMed1990

Excitatory amino acid receptors and synaptic plasticity.

Excitatory amino acid receptors are the mediators of synaptic transmission at many synapses that can undergo use-dependent modifications of synaptic efficiency. They also play an essential role in the induction of these plastic changes. Graham Collingridge and Wolf Singer describe how NMDA receptors can endow synapses with hebbian-like properties and discuss how these may be used by vertebrates for associative learning and experience-dependent modifications of synaptic connections during development. The role of AMPA receptors in the maintenance of long-term potentiation is also discussed.

Humans↗
PubMed1990

Activation of a K-252b-Sensitive Protein Kinase is Necessary for a Post-Synaptic Phase of Long-Term Potentiation in Area CA1 of Rat Hippocampus.

K-252b, a potent inhibitor of protein kinases blocked a late phase of long-term potentiation (LTP) in area CA1 of rat hippocampal slices, resulting in decremental LTP. It also prevented the slowly developing increase in sensitivity of CA1 neurons to iontophoretically administered alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) which was seen in control slices that exhibit nondecremental LTP. However, K-252b applied 60 - 180 min after the induction of LTP had no effect on the potentiated synaptic and AMPA-induced responses. A K-252b-sensitive protein kinase may therefore be involved in a slowly developing postsynaptic component of LTP.

Journal Article↗
PubMed1990

Paired-pulse depression of monosynaptic GABA-mediated inhibitory postsynaptic responses in rat hippocampus.

1. Intracellular recording techniques were used to characterize monosynaptic inhibitory postsynaptic potentials (IPSPs) and currents (IPSCs) in rat hippocampal slices and to study the mechanism of paired-pulse depression of these synaptic responses. This was achieved by stimulation in stratum radiatum close (less than 0.5 mm) to an intracellularly recorded CA1 neurone after pharmacological blockade of all excitatory synaptic transmission. 2. Under these conditions, low-frequency stimulation (0.033 Hz) evoked a pure biphasic IPSP, which had a short and constant latency to onset. This IPSP was blocked by tetrodotoxin (1 microM) suggesting that it resulted from the electrical stimulation of the axons and/or cell bodies of a monosynaptic inhibitory pathway. 3. Picrotoxin (100 microM) abolished the early component of the biphasic IPSP/C. It left an intact, pure late IPSP/C (IPSP/CB) which had a latency to onset of 29 +/- 2 ms, latency to peak of 139 +/- 4 ms, a duration of 723 +/- 135 (range 390-1730) ms and a reversal potential of -93 +/- 2 mV. The duration was highly dependent on the stimulus intensity whereas the latency to onset was largely independent of the stimulus intensity. The IPSP/CB was reduced or abolished by 1 mM-phaclofen. 4. Phaclofen (1 mM) and 2-hydroxy-saclofen (0.1-1.0 mM) reversibly depressed (60-100%) the late component of the biphasic IPSP/C and, where maximally effective, left a pure, early IPSP/C (IPSP/CA). The IPSP/CA had a latency to onset of 3 ms or less, a latency to peak of 17 +/- 1 ms, a duration of 225 +/- 3 ms and a reversal potential of -75 +/- 2 mV. 5. Two shocks of identical strength were applied in close succession to characterize, and to study the mechanisms underlying, frequency-dependent depression of inhibitory synaptic responses. Paired-pulse depression was seen for both phases of the biphasic IPSP/C and of the pure IPSP/CB, recorded in the presence of picrotoxin. Paired-pulse depression was not accompanied by changes in the reversal potential of either component, indicating that it was caused by a reduction in the two synaptic conductances. Paired-pulse depression was greater when high stimulus intensities were employed. 6. Paired stimuli were applied at separation intervals of between 5 ms and 10 s to determine the temporal profile of frequency-dependent depression. Paired-pulse depression of both IPSCA and IPSCB was most pronounced at an interstimulus interval of 100-125 ms and ceased to occur at intervals greater than 5 10s.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1989

Low-frequency activation of the NMDA receptor system can prevent the induction of LTP.

In rat hippocampal slices bathed in Mg2(+)-free medium tetanic stimulation generally failed to elicit long-term potentiation (LTP) in the Schaffer collateral-commissural pathway. However, LTP could be induced in the same slices following the re-introduction of 1 mM Mg2+. In Mg2(+)-free medium, LTP could be induced in the presence of 20 microM D-2-amino-5-phosphonovalerate (APV) but was blocked by increasing the APV concentration to 200 microM. The lower concentration of APV is sufficient to prevent N-methyl-D-aspartate (NMDA) receptor activation during low-frequency transmission but not during the tetanus. We suggest therefore, that certain types of activation of the NMDA receptor system can disable the LTP induction mechanism.

2-Amino-5-phosphonovalerate↗