Wickliffe C. Abraham

Metaplasticity: the plasticity of synaptic plasticity

In this paper, we review experimental evidence for a novel form of persistent synaptic plasticity we call metaplasticity. Metaplasticity is induced by synaptic or cellular activity, but it is not necessarily expressed as a change in the efficacy of normal synaptic transmission. Instead, it is manifest as a change in the ability to induce subsequent synaptic plasticity, such as long-term potentiation or depression. Thus, metaplasticity is a higher-order form of synaptic plasticity. Metaplasticity might involve alterations in NMDA-receptor function in some cases, but there are many other candidate mechanisms. The induction of metaplasticity complicates the interpretation of many commonly studied aspects of synaptic plasticity, such as saturation and biochemical correlates.

Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory.

Amyloid-beta precursor protein (APP) is a membrane-spanning protein with a large extracellular domain and a much smaller intracellular domain. It is the source of the amyloid-beta (Abeta) peptide found in neuritic plaques of Alzheimers disease (AD) patients. Because Abeta shows neurotoxic properties, and because familial forms of AD promote Abeta accumulation, a massive international research effort has been aimed at understanding the mechanisms of Abeta generation, catabolism and toxicity. APP, however, is an extremely complex molecule that may be a functionally important molecule in its full-length configuration, as well as being the source of numerous fragments with varying effects on neural function. For example, one fragment derived from the non-amyloidogenic processing pathway, secreted APPalpha (sAPPalpha), is neuroprotective, neurotrophic and regulates cell excitability and synaptic plasticity, while Abeta appears to exert opposing effects. Less is known about the neural functions of other fragments, but there is a growing interest in understanding the basic biology of APP as it has become recognized that alterations in the functional activity of the APP fragments during disease states will have complex effects on cell function. Indeed, it has been proposed that reductions in the level or activity of certain APP fragments, in addition to accumulation of Abeta, may play a critical role in the cognitive dysfunction associated with AD, particularly early in the course of the disease. To test and modify this hypothesis, it is important to understand the roles that full-length APP and its fragments normally play in neuronal structure and function. Here we review evidence addressing these fundamental questions, paying particular attention to the contributions that APP fragments play in synaptic transmission and neural plasticity, as these may be key to understanding their effects on learning and memory. It is clear from this literature that APP fragments, including Abeta, can exert a powerful regulation of key neural functions including cell excitability, synaptic transmission and long-term potentiation, both acutely and over the long-term. Furthermore, there is a small but growing literature confirming that these fragments correspondingly regulate behavioral learning and memory. These data indicate that a full account of cognitive dysfunction in AD will need to incorporate the actions of the full complement of APP fragments. To this end, there is an urgent need for a dedicated research effort aimed at understanding the behavioral consequences of altered levels and activity of the different APP fragments as a result of experience and disease.

Metaplasticity: tuning synapses and networks for plasticity

Synaptic plasticity is a key component of the learning machinery in the brain. It is vital that such plasticity be tightly regulated so that it occurs to the proper extent at the proper time. Activity-dependent mechanisms that have been collectively termed metaplasticity have evolved to help implement these essential computational constraints. Various intercellular signalling molecules can trigger lasting changes in the ability of synapses to express plasticity; their mechanisms of action are reviewed here, along with a consideration of how metaplasticity might affect learning and clinical conditions.

Correlations between immediate early gene induction and the persistence of long-term potentiation.

The duration of long-term potentiation in the dentate gyrus of awake rats was examined following systematic manipulation of the number of stimulus trains delivered. This was correlated with the induction of immediate early genes in separate groups of animals given identical stimulus regimes. Following 10 trains of stimulation, long-term potentiation decayed with a time constant of up to several days (long-term potentiation 2), and this correlated with the appearance of an increase in the messenger RNA and protein levels of zif/268. Increasing the number of stimulus trains resulted in a greater probability of eliciting long-term potentiation with a time constant of several weeks (long-term potentiation 3), as well as increasing the induction of zif/268, c-Jun, Jun-B, Jun-D and Fos-related proteins. When 10 trains were delivered repeatedly on up to five consecutive days, only the zif/268 protein levels showed associated changes. These data provide support for the hypothesis that long-term potentiation 3 involves mechanisms additional to those for long-term potentiation 2. One possible mechanism is altered gene expression, initiated by immediate early gene transcription factors such as zif/268 and possibly homo- or heterodimers of Fos and Jun family members, that then contributes to the stabilization or maintenance of long-term potentiation 3.

Maintenance of long-term potentiation in rat dentate gyrus requires protein synthesis but not messenger RNA synthesis immediately post-tetanization

The involvement of new protein and messenger ribonucleic acid synthesis in long-term potentiation was studied in the anaesthetized rat dentate gyrus using several inhibitors of protein synthesis (anisomycin, emetine, cycloheximide and puromycin) and an inhibitor of messenger ribonucleic acid synthesis (actinomycin D). When injected for 1 h just prior to tetanization, the four inhibitors of protein synthesis produced a mild reduction of long-term potentiation of the excitatory postsynaptic potential measured 10 min after tetanization. Anisomycin produced a significantly faster decay of long-term potentiation, while the other inhibitors had more moderate effects. Actinomycin D failed to affect long-term potentiation. In a second experiment, the time-dependency of the anisomycin effect was examined. Anisomycin injected immediately after tetanization promoted decay of long-term potentiation, but when injected after a 15-min delay, the drug had no effect. Inhibition of protein synthesis for 4 h prior to tetanization did not have any more effect on long-term potentiation than inhibition for 1 h. In no experiment was long-term potentiation of the population spike affected by drug manipulation. These results suggest that for long-term potentiation of the excitatory postsynaptic potential to be maintained for at least 3 h proteins must be synthesized from already existing messenger ribonucleic acid, and that this synthesis is mostly completed within 15 min after tetanization.

The role of immediate early genes in the stabilization of long-term potentiation.

Immediate early genes (IEGs) are a class of genes that show rapid and transient but protein synthesisindependent increases in expression to extracellular signals such as growth factors and neurotransmitters. Many IEGs code for transcription factors that have been suggested to govern the growth and differentiation of many cell types by regulating the expression of other genes. IEGs are expressed in adult neurons both constitutively and in response to afferent activity, and it has been suggested that during learning, IEGs may play a role in the signal cascade, resulting in the expression of genes critical for the consolidation of long-term memory. Long-term potentiation (LTP) is a persistent activity-dependent form of synaptic plasticity that stands as a good candidate for the mechanism of associative memory. A number of IEGs coding for transcription factors have been shown to transiently increase transcription in the dentate gyrus of rats following LTP-inducing afferent stimulation. These includezif/268 (also termedNGFI-A, Krox-24, TIS-8, andegr-l),c-fos-related genes,c-jun, junB, and junD. Of these,zif/268 appears to be the most specifically related to LTP since it is evoked under virtually all LTP-inducing situations and shows a remarkably high correlation with the duration of LTP. There are a number of outstanding questions regarding the role ofzif/268 and other IEGs in LTP, including which second messenger systems are important for activating them, which “late effector” genes are regulated by them, and the exact role these genes play, if any, in the stabilization and maintenance of LTP.

Effects of the NMDA receptor/channel antagonists CPP and MK801 on hippocampal field potentials and long-term potentiation in anesthetized rats.

The effects of the competitive and non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, 3-[(+/- )-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP) and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine maleate (MK801) were tested on hippocampal field potentials and long-term potentiation (LTP) in urethane-anesthetized rats. Neither drug had any significant effects on the dentate hilar population excitatory postsynaptic potential (EPSP) evoked by perforant path stimulation 30 or 150 min postinjection. However, both drugs produced a dose-dependent decrease in population spike amplitude at these times. Both drugs (at the highest doses) also blocked LTP when induced 150 min after administration, and this was related to a smaller response evoked during tetanization. CPP exerted similar effects on commissural-CA1 evoked responses and LTP. CPP remained an effective blocker of LTP for 6-8 h, and was still partially effective after 20-24 h. MK801 washed out more rapidly. The effect of MK801 on LTP did not depend on stimulus-evoked transmitter release during the pretetanization period. The results indicate that both CPP and MK801 have potent effects on LTP in the in vivo preparation, but that this is accompanied by an independent effect on evoked cell discharge.

Long-term potentiation and the induction of c-fos mRNA and proteins in the dentate gyrus of unanesthetized rats.

We tested the hypothesis that the nuclear proto-oncogene c-fos is involved in long-term potentiation (LTP) of the perforant path-dentate gyrus synapse in awake freely moving rats. High-frequency stimulation that produced LTP induced c-fos mRNA and protein in the dentate granule cells but not in CA1, CA3, or the entorhinal cortex. However, the degree of LTP induction did not correlate with the degree of c-fos induction. Agents that interfered with the production of LTP (e.g. NMDA antagonists) also prevented c-fos induction. Low-frequency stimulation did not lead to either LTP or c-fos induction. However, c-fos induction did not necessarily follow LTP production because some high-frequency stimulation protocols that produced good LTP did not lead to c-fos induction. Thus, c-fos induction is clearly not related to LTP production in unanaesthetized rats, but it remains to be determined if it plays some role in LTP maintenance.

Memory retention - the synaptic stability versus plasticity dilemma

Memory maintenance is widely believed to involve long-term retention of the synaptic weights that are set within relevant neural circuits during learning. However, despite recent exciting technical advances, it has not yet proved possible to confirm experimentally this intuitively appealing hypothesis. Artificial neural networks offer an alternative methodology as they permit continuous monitoring of individual connection weights during learning and retention. In such models, ongoing alterations in connection weights are required if a network is to retain previously stored material while learning new information. Thus, the duration of synaptic change does not necessarily define the persistence of a memory; rather, it is likely that a regulated balance of synaptic stability and synaptic plasticity is required for optimal memory retention in real neuronal circuits.

A double dissociation within the hippocampus of dopamine D1/D5 receptor and β-adrenergic receptor contributions to the persistence of long-term potentiation

We compared the effects of the D1/D5 receptor antagonist SCH-23390 with the beta-adrenergic receptor antagonist propranolol on the persistence of long-term potentiation in the CA1 and dentate gyrus subregions of the hippocampus. In slices, SCH-23390 but not propranolol reduced the persistence of long-term potentiation in area CA1 without affecting its induction. The drugs exerted reverse effects in the dentate gyrus, although in this case the induction of long-term potentiation was also affected by propranolol. The lack of effect of SCH-23390 on the induction and maintenance of long-term potentiation in the dentate gyrus was confirmed in awake animals. The drug also had little or no effect on the expression of inducible transcription factors. In area CA1 of awake animals, SCH-23390 blocked persistence of long-term potentiation beyond 3 h, confirming the results in slices. To rule out a differential release of catecholamines induced by our stimulation protocols between brain areas, we compared the effects of the D1/D5 agonist SKF-38393 with the beta-adrenergic agonist isoproterenol on the persistence of a weakly induced, decremental long-term potentiation in CA1 slices. SKF-38393 but not isoproterenol promoted greater persistence of long-term potentiation over a 2-h period. In contrast, isoproterenol but not SKF-38392 facilitated the induction of long-term potentiation. These data demonstrate that there is a double dissociation of the catecholamine modulation of long-term potentiation between CA1 and the dentate gyrus, suggesting that long-term potentiation in these brain areas may be differentially consolidated according to the animals behavioural state.