Long-Term Potentiation--A Decade of Progress?
17 Sep 1999-Science (American Association for the Advancement of Science)-Vol. 285, Iss: 5435, pp 1870-1874
TL;DR: A simple model is described that unifies much of the data that previously were viewed as contradictory about the molecular mechanisms of this long-lasting increase in synaptic strength in the hippocampus.
Abstract: Long-term potentiation of synaptic transmission in the hippocampus is the leading experimental model for the synaptic changes that may underlie learning and memory. This review presents a current understanding of the molecular mechanisms of this long-lasting increase in synaptic strength and describes a simple model that unifies much of the data that previously were viewed as contradictory.
Citations
More filters
TL;DR: Transcranial electrical stimulation using weak current may be a promising tool to modulate cerebral excitability in a non‐invasive, painless, reversible, selective and focal way.
Abstract: The approach taken in this study to produce localised changes of cerebral excitability in the intact human was modulation of neuronal excitability by weak electric currents applied transcranially. So far, this technique has mainly been used in animal research, primarily through modulation of the resting membrane potential (Terzuolo & Bullock, 1956; Creutzfeld et al. 1962; Eccles et al. 1962; Bindman et al. 1964; Purpura & McMurtry, 1965; Artola et al. 1990; Malenka & Nicoll, 1999). In general, cerebral excitability was diminished by cathodal stimulation, which hyperpolarises neurones. Anodal stimulation caused neuronal depolarisation, leading to an increase in excitability (Bindman et al. 1962; Purpura & McMurtry, 1965), as was shown by spontaneous neuronal discharges and the amplitudes of evoked potentials (Landau et al. 1964; Purpura & McMurtry, 1965; Gorman, 1966). However, in single cortical layers opposite effects were seen (Purpura & McMurtry, 1965), underlining the fact that the effects of DC stimulation depend on the interaction of electric flow direction and neuronal geometry. Enduring effects of 5 h and longer have been described if the stimulation itself lasts sufficiently long, about 10–30 min. These prolonged effects are not simply due to prolonged membrane potential shifts or recurrent excitation, because intermittent complete cancellation of electrical brain activity by hypothermia does not abolish them (Gartside, 1968a,b). Long-term potentiation (LTP) and long-term depression (LTD) have been proposed as the likely candidates for this phenomenon (Hattori et al. 1990; Moriwaki, 1991; Islam et al. 1995; Malenka & Nicoll, 1999).
The concept described here was an attempt to induce neuronal excitability changes in man by application of weak DC stimulation through the intact skull. It has already been demonstrated within invasive presurgical epilepsy diagnostics that intracranial currents of sufficient strength can be achieved in humans by stimulation with surface electrodes at intensities of up to 1.5 mA (Dymond et al. 1975). A suitable candidate for evaluating cortical excitability changes is transcranial magnetic stimulation (TMS), because it allows the quantification of motor-cortical neurone responses in a painless and non-invasive manner. The amplitude of the resulting motor-evoked potential (MEP) represents the excitability of the motor system. In the following, we confirm the principal possibility of altering cortical excitability by applying weak DC. Furthermore we show that systematic DC stimulation with minimum stimulation duration and intensity is necessary for an effective application of weak current in humans. This is of particular importance for inducing effects which outlast the duration of stimulation.
4,672 citations
Cites background or methods from "Long-Term Potentiation--A Decade of..."
...Long-term potentiation (LTP) and long-term depression (LTD) have been proposed as the likely candidates for this phenomenon (Hattori et al. 1990; Moriwaki, 1991; Islam et al. 1995; Malenka & Nicoll, 1999)....
[...]
...So far, this technique has mainly been used in animal research, primarily through modulation of the resting membrane potential (Terzuolo & Bullock, 1956; Creutzfeld et al. 1962; Eccles et al. 1962; Bindman et al. 1964; Purpura & McMurtry, 1965; Artola et al. 1990; Malenka & Nicoll, 1999)....
[...]
TL;DR: Neurotrophins regulate development, maintenance, and function of vertebrate nervous systems, and control synaptic function and synaptic plasticity, while continuing to modulate neuronal survival.
Abstract: Neurotrophins regulate development, maintenance, and function of vertebrate nervous systems. Neurotrophins activate two different classes of receptors, the Trk family of receptor tyrosine kinases and p75NTR, a member of the TNF receptor superfamily. Through these, neurotrophins activate many signaling pathways, including those mediated by ras and members of the cdc-42/ras/rho G protein families, and the MAP kinase, PI-3 kinase, and Jun kinase cascades. During development, limiting amounts of neurotrophins function as survival factors to ensure a match between the number of surviving neurons and the requirement for appropriate target innervation. They also regulate cell fate decisions, axon growth, dendrite pruning, the patterning of innervation and the expression of proteins crucial for normal neuronal function, such as neurotransmitters and ion channels. These proteins also regulate many aspects of neural function. In the mature nervous system, they control synaptic function and synaptic plasticity, while continuing to modulate neuronal survival.
3,968 citations
Cites background from "Long-Term Potentiation--A Decade of..."
...The enhanced efficiency of synaptic transmission observed after induction of LTP is largely mediated by an NMDA receptor-dependent increase in AMPA receptor function (reviewed in Malenka & Nicoll 1999)....
[...]
...…establishment of LTP between afferents from CA3 pyramidal cells and postsynaptic CA1 pyramidal neurons in the hippocampus have been of intense interest, as these mechanisms are believed to provide a paradigm for regulation of synaptic strength and plasticity (reviewed in Malenka & Nicoll 1999)....
[...]
...The dependence on NMDA receptor function and Ca2+ are similar to the requirements for generation of longterm potentiaion (LTP) in the hippocampus (see Malenka & Nicoll 1999)....
[...]
TL;DR: This review examines the progress made over the century in understanding the time-dependent processes that create the authors' lasting memories.
Abstract: The memory consolidation hypothesis proposed 100 years ago by Muller and Pilzecker continues to guide memory research. The hypothesis that new memories consolidate slowly over time has stimulated studies revealing the hormonal and neural influences regulating memory consolidation, as well as molecular and cellular mechanisms. This review examines the progress made over the century in understanding the time-dependent processes that create our lasting memories.
3,902 citations
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 "Long-Term Potentiation--A Decade of..."
...An intriguing hypothesis2003; Malenka and Nicoll, 1999; Soderling and Derkach, 2000)....
[...]
...The onlycellular stores (Bliss and Collingridge, 1993; Malenka and Nicoll, 1999)?...
[...]
...…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)....
[...]
...The evidence in support of a requisite role for CaMKII in LTP is compel-or does Ca2 also need to diffuse further into the spine, perhaps to cause additional release of Ca2 from intra- ling and has been extensively reviewed elsewhere (Lisman et al., 2002; Malenka and Nicoll, 1999)....
[...]
...Signaling mol-ity-dependent changes in AMPAR trafficking (Bredt and Nicoll, 2003; Malenka and Nicoll, 1999; Malinow and ecules that are thought to link the activity that induces LTP to the nucleus include PKA, CaMKIV, and MAPK,Malenka, 2002; Song and Huganir, 2002)....
[...]
TL;DR: Here, a conceptual framework for the contribution of plasticity in primary sensory and dorsal horn neurons to the pathogenesis of pain is developed, identifying distinct forms of Plasticity, which are term activation, modulation, and modification, that by increasing gain, elicit pain hypersensitivity.
Abstract: We describe those sensations that are unpleasant, intense, or distressing as painful. Pain is not homogeneous, however, and comprises three categories: physiological, inflammatory, and neuropathic pain. Multiple mechanisms contribute, each of which is subject to or an expression of neural plasticity-the capacity of neurons to change their function, chemical profile, or structure. Here, we develop a conceptual framework for the contribution of plasticity in primary sensory and dorsal horn neurons to the pathogenesis of pain, identifying distinct forms of plasticity, which we term activation, modulation, and modification, that by increasing gain, elicit pain hypersensitivity.
3,543 citations
References
More filters
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.
11,123 citations
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
TL;DR: The sequential combination of spontaneously generated and experience-dependent neural activity endows the brain with an ongoing ability to accommodate to dynamically changing inputs during development and throughout life.
Abstract: Vision is critical for the functional and structural maturation of connections in the mammalian visual system. Visual experience, however, is a subset of a more general requirement for neural activity in transforming immature circuits into the organized connections that subserve adult brain function. Early in development, internally generated spontaneous activity sculpts circuits on the basis of the brain's "best guess" at the initial configuration of connections necessary for function and survival. With maturation of the sense organs, the developing brain relies less on spontaneous activity and increasingly on sensory experience. The sequential combination of spontaneously generated and experience-dependent neural activity endows the brain with an ongoing ability to accommodate to dynamically changing inputs during development and throughout life.
2,880 citations
TL;DR: After induction of long-lasting (but not short-lasting) functional enhancement of synapses in area CA1, new spines appear on the postsynaptic dendrite, whereas in control regions on the same dendrites or in slices where long-term potentiation was blocked, no significant spine growth occurred.
Abstract: Long-term enhancement of synaptic efficacy in the hippocampus is an important model for studying the cellular mechanisms of neuronal plasticity, circuit reorganization, and even learning and memory. Although these long-lasting functional changes are easy to induce, it has been very difficult to demonstrate that they are accompanied or even caused by morphological changes on the subcellular level. Here we combined a local superfusion technique with two-photon imaging, which allowed us to scrutinize specific regions of the postsynaptic dendrite where we knew that the synaptic changes had to occur. We show that after induction of long-lasting (but not short-lasting) functional enhancement of synapses in area CA1, new spines appear on the postsynaptic dendrite, whereas in control regions on the same dendrite or in slices where long-term potentiation was blocked, no significant spine growth occurred.
1,749 citations
TL;DR: W Whole cell recordings reveal that postsynaptic mechanisms, including N-methyl-D-aspartate (NMDA) receptor function, are intact and are therefore a suitable model for studying the relation between LTP and learning processes.
Abstract: As a first step in a program to use genetically altered mice in the study of memory mechanisms, mutant mice were produced that do not express the alpha-calcium-calmodulin-dependent kinase II (alpha-CaMKII). The alpha-CaMKII is highly enriched in postsynaptic densities of hippocampus and neocortex and may be involved in the regulation of long-term potentiation (LTP). Such mutant mice exhibited mostly normal behaviors and presented no obvious neuroanatomical defects. Whole cell recordings reveal that postsynaptic mechanisms, including N-methyl-D-aspartate (NMDA) receptor function, are intact. Despite normal postsynaptic mechanisms, these mice are deficient in their ability to produce LTP and are therefore a suitable model for studying the relation between LTP and learning processes.
1,467 citations