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.

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

Changing the strength of connections between neurons is widely assumed to be the mechanism by which memory traces are encoded and stored in the central nervous system. In its most general form, the synaptic plasticity and memory hypothesis states that "activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation and is both necessary and sufficient for the infor- mation storage underlying the type of memory mediated by the brain area in which that plasticity is observed." We outline a set of criteria by which this hypothesis can be judged and describe a range of experimental strategies used to investigate it. We review both classical and newly discovered properties of synaptic plasticity and stress the importance of the neural architecture and synaptic learning rules of the network in which it is embedded. The greater part of the article focuses on types of memory mediated by the hippocampus, amygdala, and cortex. We conclude that a wealth of data supports the notion that synaptic plasticity is necessary for learning and memory, but that little data currently supports the notion of sufficiency.

Synaptic plasticity and memory: an evaluation of the hypothesis

It has been clear for almost two decades that cortical representations in adult animals are not fixed entities, but rather, are dynamic and are continuously modified by experience. The cortex can preferentially allocate area to represent the particular peripheral input sources that are proportionally most used. Alterations in cortical representations appear to underlie learning tasks dependent on the use of the behaviorally important peripheral inputs that they represent. The rules governing this cortical representational plasticity following manipulations of inputs, including learning, are increasingly well understood. In parallel with developments in the field of cortical map plasticity, studies of synaptic plasticity have characterized specific elementary forms of plasticity, including associative long-term potentiation and long-term depression of excitatory postsynaptic potentials. Investigators have made many important strides toward understanding the molecular underpinnings of these fundamental plasticity processes and toward defining the learning rules that govern their induction. The fields of cortical synaptic plasticity and cortical map plasticity have been implicitly linked by the hypothesis that synaptic plasticity underlies cortical map reorganization. Recent experimental and theoretical work has provided increasingly stronger support for this hypothesis. The goal of the current paper is to review the fields of both synaptic and cortical map plasticity with an emphasis on the work that attempts to unite both fields. A second objective is to highlight the gaps in our understanding of synaptic and cellular mechanisms underlying cortical representational plasticity.

/pdf/cortical-plasticity-from-synapses-to-maps-2j9eoi9428.pdf

CORTICAL PLASTICITY: From Synapses to Maps

The physiology of excitatory amino acids in the vertebrate central nervous system.

We tested a theoretical prediction that patterns of excitatory input activity that consistently fail to activate target neurons sufficiently to induce synaptic potentiation will instead cause a specific synaptic depression. To realize this situation experimentally, the Schaffer collateral projection to area CA1 in rat hippocampal slices was stimulated electrically at frequencies ranging from 0.5 to 50 Hz. Nine hundred pulses at 1-3 Hz consistently yielded a depression of the CA1 population excitatory postsynaptic potential that persisted without signs of recovery for greater than 1 hr after cessation of the conditioning stimulation. This long-term depression was specific to the conditioned input, ruling out generalized changes in postsynaptic responsiveness or excitability. Three lines of evidence suggest that this effect is accounted for by a modification of synaptic effectiveness rather than damage to or fatigue of the stimulated inputs. First, the effect was dependent on the stimulation frequency; 900 pulses at 10 Hz caused no lasting change, and at 50 Hz a synaptic potentiation was usually observed. Second, the depressed synapses continued to support long-term potentiation in response to a high-frequency tetanus. Third, the effects of conditioning stimulation could be prevented by application of NMDA receptor antagonists. Thus, our data suggest that synaptic depression can be triggered by prolonged NMDA receptor activation that is below the threshold for inducing synaptic potentiation. We propose that this mechanism is important for the modifications of hippocampal response properties that underlie some forms of learning and memory.

https://www.pnas.org/content/pnas/89/10/4363.full.pdf

Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade.

BRIEF trains of electrical stimulation delivered to any one of several hippocampal pathways often result in immediate and long-lasting enhancement of subsequent postsynaptic responses elicited by that pathway1–5. The unusual characteristics of these effects suggest that theories of long-term potentiation (specifically changes in transmitter release by the presynaptic terminal) which have evolved from work on invertebrate and neuromusclar preparations may not be appropriate to explain synaptic plasticity in hippocampus. We report here the results of experiments intended to examine the postsynaptic consequences of repetitive stimulation. We found that potentiation of one afferent tended to depress the target cell's responses to a second test input.

Heterosynaptic depression: a postsynaptic correlate of long-term potentiation

GDEE antagonism of iontophoretic amino acid excitations in the intact hippocampus and in the hippocampal slice preparation

HIPPOCAMPAL synapses show an unusual degree of physiological plasticity. Relatively modest levels of repetitive stimulation cause considerable enhancement in subsequent responses to single pulse stimulation, and this potentiation lasts for hours and even days1–6. These findings, which have now been replicated in several laboratories, have aroused much interest, first because they seem to represent an excellent starting point for the analysis of synaptic plasticity in mammalian brain, and second, because their rapid development and persistence suggest that they may be related to processes involved in behavioural plasticity. The studies reported here represent an attempt to analyse the mechanisms underlying physiological plasticity in the hippocampus, in particular the locus and anatomical specificity of the effect. The change in magnitude of response which occurs after repetitive stimulation could reflect either presynaptic or postsynaptic adjustment. If the latter were the case, the change might involve a particular dendritic region innervated by the stimulated input, or alteration in the status of the entire postsynaptic neurone. Seeking data relevant to these questions, we have measured the effects of glutamic acid applied iontophoretically to different levels of the dendritic trees of the pyramidal cells before and after potentiation of the extracellular postsynaptic response.

Long term potentiation is accompanied by a reduction in dendritic responsiveness to glutamic acid.

Long lasting changes in the spontaneous activity of hippocampal neurons following stimulation of the entorhinal cortex

To investigate the release of adenine compounds from defined neuronal pathways, we employed a hippocampal slice preparation in which a selective-loading of the releasable pools was achieved in vivo with the aid of axonal transport. By injecting radioactive adenosine stereotaxically into the entorhinal cortex, the major afferent system to the dentate gyrus (the perforant path) was loaded within 20–36 h, at which time the rats were killed and hippocampal slices were prepared. The efflux of radioactive material, as recovered from the perfusate and measured in a scintillation counter, was found to be significantly increased in response to electrophysiologically controlled stimulation of the perforant path but not to stimulation of an alternative fiber tract, the fimbria. These findings provide supportive and more direct evidence for an activation-coupled release of adenosine derivatives from presynaptic sites in the central nervous system.

Valentin Gribkoff

Papers

Heterosynaptic depression: a postsynaptic correlate of long-term potentiation

GDEE antagonism of iontophoretic amino acid excitations in the intact hippocampus and in the hippocampal slice preparation

Long term potentiation is accompanied by a reduction in dendritic responsiveness to glutamic acid.

Long lasting changes in the spontaneous activity of hippocampal neurons following stimulation of the entorhinal cortex

A Combined In Vivo/In Vitro Study of the Presynaptic Release of Adenosine Derivatives in the Hippocampus