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The induction of long-term potentiation (LTP) in the dentate gyrus of the hippocampus is associated with a rapid and robust transcription of the immediate early gene Zif268 . We used a mutant mouse with a targeted disruption of Zif268 to ask whether this gene, which encodes a zinc finger transcription factor, is required for the maintenance of late LTP and for the expression of long-term memory. We show that whereas mutant mice exhibit early LTP in the dentate gyrus, late LTP is absent when measured 24 and 48 hours after tetanus in the freely moving animal. In both spatial and non-spatial learning tasks, short-term memory remained intact, whereas performance was impaired in tests requiring long-term memory. Thus, Zif268 is essential for the transition from short- to long-term synaptic plasticity and for the expression of long-term memories.

We summarize the reviews and research papers submitted by speakers at a discussion meeting on Synaptic Plasticity in Health and Disease held at the Royal Society, London on 2–3 December 2013, and a subsequent satellite meeting convened at the Royal Society/Kavli Centre at Chicheley Hall on 4–5 December 2013. Together, these contributions give an overview of current research and controversies in a vibrant branch of neuroscience with important implications for the understanding of many forms of learning and memory, and a wide spectrum of neurological and cognitive disorders.

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.

THE process of learning involves stable changes in synaptic efficacy for which long-term potentiation (LTP) 1 provides a widely adopted mammalian model. Synaptic modification induced by learning or LTP may involve the action of cell adhesion molecules 2–4 . One such candidate is the ubiquitous neuronal glycoprotein Thy-1 (refs 5, 6). In mice in which the gene encoding Thy-1 has been inactivated, we find a regionally selective impairment of LTP in vivo in the hippocampal formation: LTP is normal in area CA1 but strongly inhibited in the dentate gyrus. Spatial learning by Thy-1-deficient mice, as assessed in the watermaze 7 , is unimpaired. Thus LTP in the cortical input to the dentate gyrus seems not to be required for spatial learning.

Long-term potentiation (LTP) is a widely studied model of the synaptic basis of information storage in the mammalian brain. The induction of LTP is triggered by the postsynaptic entry of calcium through the channel associated with the N-methyl-D-aspartate (NMDA) receptor, whereas its maintenance is mediated, at least in part, by presynaptic mechanisms. To explain how postsynaptic events can lead to an increase in transmitter release, we have postulated the existence of a retrograde messenger to carry information from the postsynaptic side of the synapse to recently active presynaptic terminals. Candidates for a retrograde messenger include arachidonic acid or one of its lipoxygenase metabolites. Here we report that weak activation of the perforant path, when given in the presence of arachidonic acid, leads to a slow-onset persistent increase in synaptic efficacy both in vivo and in vitro. The activity-dependent potentiation thus produced is accompanied by an increase in the release of glutamate, and is non-additive with tetanus-induced LTP. These observations indicate a role for arachidonic acid as a retrograde messenger in the later, but not the initial, stages of LTP.

We investigated synaptic communication and plasticity in hippocampal slices from mice overexpressing mutated 695-amino-acid human amyloid precursor protein (APP 695 SWE), which show behavioral and histopathological abnormalities simulating Alzheimer's disease. Although aged APP transgenic mice exhibit normal fast synaptic transmission and short term plasticity, they are severely impaired in in - vitro and in - vivo long-term potentiation (LTP) in both the CA1 and dentate gyrus regions of the hippocampus. The LTP deficit was correlated with impaired performance in a spatial working memory task in aged transgenics. These deficits are accompanied by minimal or no loss of presynaptic or postsynaptic elementary structural elements in the hippocampus, suggesting that impairments in functional synaptic plasticity may underlie some of the cognitive deficits in these mice and, possibly, in Alzheimer's patients.

Here's a question often debated in the examination halls and coffee rooms of neuroscience and psychology departments during the last two decades: Does long-term potentiation (LTP)--the enduring enhancement of synaptic efficacy triggered by bursts of high-frequency stimulation--provide the cellular basis for hippocampal-dependent behavioral learning? Or, to be more succinct, does LTP=learning? The question is easily posed, but--as might be expected of an issue lysing at the boundary of the physiological and the cognitive--an unequivocal answer is proving remarkably elusive. On page 2038 of this issue, Moser and colleagues revisit the problem by using an approach first attempted around 10 years ago in the laboratory of McNaughton and Barnes.

We have used a glutamate-specific dialysis electrode to obtain real-time measurements of changes in the concentration of glutamate in the extracellular space of the hippocampus during low-frequency stimulation and following the induction of long-term potentiation (LTP). In the dentate gyrus, stimulation of the perforant path at 2 Hz for 2 min produced a transient increase in glutamate current relative to the basal value at control rates of stimulation (0.033 Hz). This activity-dependent glutamate current was significantly enhanced 35 and 90 min after the induction of LTP. The maximal 2 Hz signal was obtained during post-tetanic potentiation (PTP). There was also a more gradual increase in the basal level of extracellular glutamate following the induction of LTP. Both the basal and activity-dependent increases in glutamate current induced by tetanic stimulation were blocked by local infusion of the N-methyl-D-aspartate receptor antagonist D-APV. In areas CA1 and CA3 we were unable to detect a 2 Hz glutamate signal either before or after the induction of LTP, possibly owing to a more avid uptake of glutamate in the pyramidal cell fields. These results demonstrate that LTP in the dentate gyrus is associated with a greater concentration of extracellular glutamate following activation of potentiated synapses, either because potentiated synapses release more transmitter per impulse, or because of reduced uptake by glutamate transporters. We present arguments favouring increased release rather than decreased uptake.

Synaptic efficacy following long‐term potentiation (LTP) and memory consolidation is associated with changes in the expression of immediate early genes (IEGs). These changes are often accompanied by increased expression of glial fibrillary acidic protein (GFAP). While the protein products of the majority of IEGs are mainly restricted to the cell body, Arg3.1/Arc product is rapidly delivered to dendrites, where it accumulates close to synaptic sites. Arg3.1/Arc protein was originally considered neurone specific; however, we have recently found Arg3.1/Arc immunoreactivity (Arg3.1/Arc‐IR) within glial cells and demonstrated its increased expression after LTP in the hippocampal dentate gyrus (DG). Here, we have further investigated this novel finding, using electron microscopic immunocytochemistry to determine the localization and sub‐cellular distribution of Arg3.1/Arc protein in GFAP positive glia (GFAP‐IR) in the DG. Arg3.1/Arc labelling was seen prominently in GFAP‐IR glial cell bodies and in large‐ and medium‐sized glial filamentous processes. GFAP‐labelled medium–small peri‐synaptic glial profiles also displayed Arg3.1/Arc‐IR; however, the very thin and distal glial filaments only displayed Arc‐IR. Arc‐IR was distributed throughout the cytoplasm, often associated with GFAP filaments, and along the plasma membrane of glial processes. Peri‐synaptic glial Arg3.1/Arc‐IR processes were apposed to pre‐ and/or post‐synaptic profiles at asymmetric axospinous synapses. These data, taken with our earlier study which provided evidence for an increase in astrocytic Arg3.1/Arc‐IR after the induction of LTP, suggest a role for glial Arg3.1/Arc in structural and synaptic plasticity which may be critical for the maintenance of cognitive functions.

In the mid-1960s, it was generally agreed that the engram, the neural trace of previously experienced events, must be encoded by Hebb-like neurons in which synaptic efficacy could be modified by activity. Here, I describe my attempts as a PhD student at McGill University, Montreal, to find rules governing cortical plasticity in the neocortex, and having failed, why the hippocampus seemed to offer a far better prospect.