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Journal ArticleDOI

A synaptic model of memory: long-term potentiation in the hippocampus

07 Jan 1993-Nature (Nature Publishing Group)-Vol. 361, Iss: 6407, pp 31-39
TL;DR: The best understood form of long-term potentiation is induced by the activation of the N-methyl-d-aspartate receptor complex, which allows electrical events at the postsynaptic membrane to be transduced into chemical signals which, in turn, are thought to activate both pre- and post Synaptic mechanisms to generate a persistent increase in synaptic strength.
Abstract: Long-term potentiation of synaptic transmission in the hippocampus is the primary experimental model for investigating the synaptic basis of learning and memory in vertebrates. The best understood form of long-term potentiation is induced by the activation of the N-methyl-D-aspartate receptor complex. This subtype of glutamate receptor endows long-term potentiation with Hebbian characteristics, and allows electrical events at the postsynaptic membrane to be transduced into chemical signals which, in turn, are thought to activate both pre- and postsynaptic mechanisms to generate a persistent increase in synaptic strength.
Citations
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Journal ArticleDOI
TL;DR: The field of neuroscience has, after a long period of looking the other way, again embraced emotion as an important research area, and much of the progress has come from studies of fear, and especially fear conditioning as mentioned in this paper.
Abstract: The field of neuroscience has, after a long period of looking the other way, again embraced emotion as an important research area. Much of the progress has come from studies of fear, and especially fear conditioning. This work has pin- pointed the amygdala as an important component of the system involved in the acqui- sition, storage, and expression of fear memory and has elucidated in detail how stimuli enter, travel through, and exit the amygdala. Some progress has also been made in understanding the cellular and molecular mechanisms that underlie fear conditioning, and recent studies have also shown that the findings from experimental animals apply to the human brain. It is important to remember why this work on emotion succeeded where past efforts failed. It focused on a psychologically well-defined aspect of emo- tion, avoided vague and poorly defined concepts such as "affect," "hedonic tone," or "emotional feelings," and used a simple and straightforward experimental approach. With so much research being done in this area today, it is important that the mistakes of the past not be made again. It is also time to expand from this foundation into broader aspects of mind and behavior

7,347 citations

Journal ArticleDOI
TL;DR: The results underscore the importance of precise spike timing, synaptic strength, and postsynaptic cell type in the activity-induced modification of central synapses and suggest that Hebb’s rule may need to incorporate a quantitative consideration of spike timing that reflects the narrow and asymmetric window for the induction of synaptic modification.
Abstract: In cultures of dissociated rat hippocampal neurons, persistent potentiation and depression of glutamatergic synapses were induced by correlated spiking of presynaptic and postsynaptic neurons. The relative timing between the presynaptic and postsynaptic spiking determined the direction and the extent of synaptic changes. Repetitive postsynaptic spiking within a time window of 20 msec after presynaptic activation resulted in long-term potentiation (LTP), whereas postsynaptic spiking within a window of 20 msec before the repetitive presynaptic activation led to long-term depression (LTD). Significant LTP occurred only at synapses with relatively low initial strength, whereas the extent of LTD did not show obvious dependence on the initial synaptic strength. Both LTP and LTD depended on the activation of NMDA receptors and were absent in cases in which the postsynaptic neurons were GABAergic in nature. Blockade of L-type calcium channels with nimodipine abolished the induction of LTD and reduced the extent of LTP. These results underscore the importance of precise spike timing, synaptic strength, and postsynaptic cell type in the activity-induced modification of central synapses and suggest that Hebb’s rule may need to incorporate a quantitative consideration of spike timing that reflects the narrow and asymmetric window for the induction of synaptic modification.

4,382 citations


Cites background or result from "A synaptic model of memory: long-te..."

  • ...This dependence of synaptic potentiation on the activation of NMDA receptors is similar to that found for LTP in the CA1 region of the hippocampus and several other brain areas (Bliss and Collingridge, 1993; Malenka and Nicoll, 1993)....

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  • ...Repetitive electrical activity can induce a persistent increase or decrease of synaptic efficacy in various parts of the nervous system, commonly referred to as long-term potentiation (LTP) and long-term depression (LTD), respectively (Bliss and Lfmo, 1973; Levy and Steward, 1983; Siegelbaum and Kandel, 1991; Bliss and Collingridge, 1993; Linden and Connor, 1995; Nicoll and Malenka, 1995)....

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  • ...…in various parts of the nervous system, commonly referred to as long-term potentiation (LTP) and long-term depression (LTD), respectively (Bliss and Lfmo, 1973; Levy and Steward, 1983; Siegelbaum and Kandel, 1991; Bliss and Collingridge, 1993; Linden and Connor, 1995; Nicoll and Malenka, 1995)....

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Journal ArticleDOI
TL;DR: The application of molecular cloning technology to the study of the glutamate receptor system has led to an explosion of knowledge about the structure, expression, and function of this most important fast excitatory transmitter system in the mammalian brain.
Abstract: The application of molecular cloning technology to the study of the glutamate receptor system has led to an explosion of knowledge about the structure, expression, and function of this most important fast excitatory transmitter system in the mammalian brain. The first functional ionotropic glutamate receptor was cloned in 1989 (Hollmann et al 1989) , and the results of this molecular-based approach over the past three years are the focus of this review. We discuss the implications of and the new questions raised by this work-which is probably only a glance at this fascinating and complex signaling system found in brains from the snails to man. Glutamate receptors are found throughout the mammalian brain, where they constitute the major excitatory transmitter system. The longest-known and best-studied glutamate receptors are ligand-gated ion channels, also called ionotropic glutamate receptors , which are permeable to cations. They have traditionally been classified into three broad subtypes based upon pharmaco­ logical and electrophysiological data: a-amino-3-hydroxy-5-methyl-4isoxazole propionate (AMPA) receptors, kainate (KA) receptors , and N-methyl-D-aspartate (NMDA) receptors. Recently, however, a family of G protein-coupled glutamate receptors , which are also called metabotropic glutamate or transl -aminocyclopentanel ,3-dicarboxylate (tACPD) recep­ tors, was identified (Sugiyama et al 1987) . (For reviews of the classification and the pharmacological and electrophysiological properties of glutamate receptors see Mayer & Westbrook 1987, Collingridge & Lester 1989, Honore 1989, Monaghan et al 1989, Wroblewski & Danysz 1 989, Hansen &

4,079 citations

Journal ArticleDOI
31 Jul 2003-Neuron
TL;DR: The recapitulation of salient features of AD in these mice clarifies the relationships between Abeta, synaptic dysfunction, and tangles and provides a valuable model for evaluating potential AD therapeutics as the impact on both lesions can be assessed.

3,811 citations


Cites background from "A synaptic model of memory: long-te..."

  • ...The PS1-KI mice, however, were not significantly different thought to underlie learning and memory (Bliss and Collingridge, 1993), was investigated in the CA1 hippocam-from the 3 Tg-AD mice....

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Journal ArticleDOI
30 Sep 2004-Neuron
TL;DR: This work reviews those forms of LTP and LTD for which mechanisms have been most firmly established and examples are provided that show how these mechanisms can contribute to experience-dependent modifications of brain function.

3,767 citations


Cites background from "A synaptic model of memory: long-te..."

  • ...A modulator is for LTP (Bliss and Collingridge, 1993; Hu et al., 1987; Linden and Routtenberg, 1989; Malenka and Nicoll,a factor that can alter LTP but is not essential for its occurrence....

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  • ...The onlycellular stores (Bliss and Collingridge, 1993; Malenka and Nicoll, 1999)?...

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  • ...…during postsynaptic depolarization which, ex- perimentally, can be achieved using any number of dif- stimulation activates intracellular signaling and expression mechanisms not elicited by a pairing protocol (inferent induction protocols (Bliss and Collingridge, 1993; Malenka and Nicoll, 1999)....

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References
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Journal ArticleDOI
TL;DR: The after‐effects of repetitive stimulation of the perforant path fibres to the dentate area of the hippocampal formation have been examined with extracellular micro‐electrodes in rabbits anaesthetized with urethane.
Abstract: 1. The after-effects of repetitive stimulation of the perforant path fibres to the dentate area of the hippocampal formation have been examined with extracellular micro-electrodes in rabbits anaesthetized with urethane.2. In fifteen out of eighteen rabbits the population response recorded from granule cells in the dentate area to single perforant path volleys was potentiated for periods ranging from 30 min to 10 hr after one or more conditioning trains at 10-20/sec for 10-15 sec, or 100/sec for 3-4 sec.3. The population response was analysed in terms of three parameters: the amplitude of the population excitatory post-synaptic potential (e.p.s.p.), signalling the depolarization of the granule cells, and the amplitude and latency of the population spike, signalling the discharge of the granule cells.4. All three parameters were potentiated in 29% of the experiments; in other experiments in which long term changes occurred, potentiation was confined to one or two of the three parameters. A reduction in the latency of the population spike was the commonest sign of potentiation, occurring in 57% of all experiments. The amplitude of the population e.p.s.p. was increased in 43%, and of the population spike in 40%, of all experiments.5. During conditioning at 10-20/sec there was massive potentiation of the population spike (;frequency potentiation'). The spike was suppressed during stimulation at 100/sec. Both frequencies produced long-term potentiation.6. The results suggest that two independent mechanisms are responsible for long-lasting potentiation: (a) an increase in the efficiency of synaptic transmission at the perforant path synapses; (b) an increase in the excitability of the granule cell population.

7,008 citations

Journal ArticleDOI
24 Nov 1988-Nature
TL;DR: It is reported here that by acting on NMDA (N-methyl-D-aspartate) receptors on cerebellar cells, glutamate induces the release of a diffusible messenger with strikingly similar properties to EDRF that accounts for the cGMP responses that take place following NMDA receptor activation.
Abstract: In the vascular system, endothelium-derived relaxing factor (EDRF) is the name of the local hormone released from endothelial cells in response to vasodilators such as acetylcholine, bradykinin and histamine. It diffuses into underlying smooth muscle where it causes relaxation by activating guanylate cyclase, so producing a rise in cyclic GMP levels. It has been known for many years that in the central nervous system (CNS) the excitatory neurotransmitter glutamate can elicit large increases in cGMP levels, particularly in the cerebellum where the turnover rate of cGMP is low. Recent evidence indicates that cell-cell interactions are involved in this response. We report here that by acting on NMDA (N-methyl-D-aspartate) receptors on cerebellar cells, glutamate induces the release of a diffusible messenger with strikingly similar properties to EDRF. This messenger is released in a Ca2+-dependent manner and its activity accounts for the cGMP responses that take place following NMDA receptor activation. In the CNS, EDRF may link activation of postsynaptic NMDA receptors to functional modifications in neighbouring presynaptic terminals and glial cells.

2,581 citations

Journal ArticleDOI
TL;DR: Results indicate that the synaptic receptor in the Schaffer collateral‐commissural pathway may be of the kainate or quisqualate type and although NMA receptors do not appear to be involved in normal synaptic transmission in this pathway they may play a role in synaptic plasticity.
Abstract: 1. The effects of excitatory amino acids and some antagonists applied by ionophoresis to stratum radiatum in the CA1 region of rat hippocampal slices were examined on the locally recorded field e.p.s.p. evoked by stimulation of the Schaffer collateral-commissural projection. 2. L-glutamate, L-aspartate and the more potent and selective excitatory amino acids quisqualate, kainate and N-methyl-DL-aspartate (NMA) depressed the e.p.s.p., presumably through depolarization and/or a change in membrane conductance. 3. The depression induced by kainate considerably outlasted the period of ejection whereas NMA depressions were rapidly reversible and were often followed by a potentiation of the e.p.s.p. In higher doses NMA also depressed the presynaptic fibre volley. The possible involvement of these effects in neurotoxicity and synaptic plasticity is raised. 4. The selective NMA antagonist, DL-2-amino-5-phosphonovalerate (APV) applied in doses which abolished responses to NMA, had no effect on the e.p.s.p. but prevented long term potentiation (l.t.p.) of synaptic transmission evoked by high frequency stimulation of the Schaffer collateral-commissural pathway. Other antagonists which had little or no effect on normal synaptic transmission included D-alpha-aminoadipate (DAA), the optical isomers of 2-amino-4-phosphonobutyrate (APB) and L-glutamate diethylester (GDEE). 5. In contrast, gamma-D-glutamylglycine (DGG), applied in amounts which affected quisqualate and kainate actions as well as those of NMA, was an effective synaptic antagonist whilst having no effect on the presynaptic fibre volley. 6. These results indicate that the synaptic receptor in the Schaffer collateral-commissural pathway may be of the kainate or quisqualate type. Although NMA receptors do not appear to be involved in normal synaptic transmission in this pathway they may play a role in synaptic plasticity. The interaction of L-glutamate and L-aspartate with these receptors is discussed.

2,236 citations

Journal ArticleDOI
01 Jan 1992-Neuron

1,830 citations

Journal ArticleDOI
01 Jan 1986-Nature
TL;DR: It is directly demonstrated that excitatory amino acids acting at NMDA receptors on spinal cord neurones increase the intracellular Ca2+ activity, measured using the indicator dye arsenazo III, and that this is the result of Ca2- influx through NMDA receptor channels.
Abstract: Excitatory amino acids act via receptor subtypes in the mammalian central nervous system (CNS). The receptor selectively activated by N-methyl-D-aspartic acid (NMDA) has been best characterized using voltage-clamp and single-channel recording; the results suggest that NMDA receptors gate channels that are permeable to Na+, K+ and other monovalent cations. Various experiments suggest that Ca2+ flux is also associated with the activation of excitatory amino-acid receptors on vertebrate neurones. Whether Ca2+ enters through voltage-dependent Ca2+ channels or through excitatory amino-acid-activated channels of one or more subtype is unclear. Mg2+ can be used to distinguish NMDA-receptor-activated channels from voltage-dependent Ca2+ channels, because at micromolar concentrations Mg2+ has little effect on voltage-dependent Ca2+ channels while it enters and blocks NMDA receptor channels. Marked differences in the potency of other divalent cations acting as Ca2+ channel blockers compared with their action as NMDA antagonists also distinguish the NMDA channel from voltage-sensitive Ca2+ channels. However, we now directly demonstrate that excitatory amino acids acting at NMDA receptors on spinal cord neurones increase the intracellular Ca2+ activity, measured using the indicator dye arsenazo III, and that this is the result of Ca2+ influx through NMDA receptor channels. Kainic acid (KA), which acts at another subtype of excitatory amino-acid receptor, was much less effective in triggering increases in intracellular free Ca2+.

1,712 citations