A nitric oxide-independent and beta-adrenergic receptor-sensitive form of metaplasticity limits theta-frequency stimulation-induced LTP in the hippocampal CA1 region

The induction of long-term potentiation (LTP) and long-term depression (LTD) at excitatory synapses in the hippocampus can be strongly modulated by patterns of synaptic stimulation that otherwise have no direct effect on synaptic strength. Likewise, patterns of synaptic stimulation that induce LTP or LTD not only modify synaptic strength but can also induce lasting changes that regulate how synapses will respond to subsequent trains of stimulation. Collectively known as metaplasticity, these activity-dependent processes that regulate LTP and LTD induction allow the recent history of synaptic activity to influence the induction of activity-dependent changes in synaptic strength and may thus have an important role in information storage during memory formation. To explore the cellular and molecular mechanisms underlying metaplasticity, we investigated the role of metaplasticity in the induction of LTP by υ-frequency (5-Hz) synaptic stimulation in the hippocampal CA1 region. Our results show that brief trains of υ-frequency stimulation not only induce LTP but also activate a process that inhibits the induction of additional LTP at potentiated synapses. Unlike other forms of metaplasticity, the inhibition of LTP induction at potentiated synapses does not appear to arise from activity-dependent changes in NMDA receptor function, does not require nitric oxide signaling, and is strongly modulated by β-adrenergic receptor activation. Together with previous findings, our results indicate that mechanistically distinct forms of metaplasticity regulate LTP induction and suggest that one way modulatory transmitters may act to regulate synaptic plasticity is by modulating metaplasticity.     

'Silent' priming of translation-dependent LTP by ß-adrenergic receptors involves phosphorylation and recruitment of AMPA receptors

The capacity for long-term changes in synaptic efficacy can be altered by prior synaptic activity, a process known as "metaplasticity." Activation of receptors for modulatory neurotransmitters can trigger downstream signaling cascades that persist beyond initial receptor activation and may thus have metaplastic effects. Because activation of β-adrenergic receptors (β-ARs) strongly enhances the induction of long-term potentiation (LTP) in the hippocampal CA1 region, we examined whether activation of these receptors also had metaplastic effects on LTP induction. Our results show that activation of β-ARs induces a protein synthesis-dependent form of metaplasticity that primes the future induction of late-phase LTP by a subthreshold stimulus. β-AR activation also induced a long-lasting increase in phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) GluA1 subunits at a protein kinase A (PKA) site (S845) and transiently activated extracellular signal-regulated kinase (ERK). Consistent with this, inhibitors of PKA and ERK blocked the metaplastic effects of β-AR activation. β-AR activation also induced a prolonged, translation-dependent increase in cell surface levels of GluA1 subunit-containing AMPA receptors. Our results indicate that β-ARs can modulate hippocampal synaptic plasticity by priming synapses for the future induction of late-phase LTP through up-regulation of translational processes, one consequence of which is the trafficking of AMPARs to the cell surface.     

Neural circuitry and plasticity mechanisms underlying delay eyeblink conditioning

Pavlovian eyeblink conditioning has been used extensively as a model system for examining the neural mechanisms underlying associative learning. Delay eyeblink conditioning depends on the intermediate cerebellum ipsilateral to the conditioned eye. Evidence favors a two-site plasticity model within the cerebellum with long-term depression of parallel fiber synapses on Purkinje cells and long-term potentiation of mossy fiber synapses on neurons in the anterior interpositus nucleus. Conditioned stimulus and unconditioned stimulus inputs arise from the pontine nuclei and inferior olive, respectively, converging in the cerebellar cortex and deep nuclei. Projections from subcortical sensory nuclei to the pontine nuclei that are necessary for eyeblink conditioning are beginning to be identified, and recent studies indicate that there are dynamic interactions between sensory thalamic nuclei and the cerebellum during eyeblink conditioning. Cerebellar output is projected to the magnocellular red nucleus and then to the motor nuclei that generate the blink response(s). Tremendous progress has been made toward determining the neural mechanisms of delay eyeblink conditioning but there are still significant gaps in our understanding of the necessary neural circuitry and plasticity mechanisms underlying cerebellar learning.     

Morphological changes in dendritic spines of Purkinje cells associated with motor learning

Experience-dependent changes of spine structure and number may contribute to long-term memory storage. Although several studies demonstrated structural spine plasticity following associative learning, there is limited evidence associating motor learning with alteration of spine morphology. Here, we investigated this issue in the cerebellar Purkinje cells using high voltage electron microscopy (HVEM). Adult rats were trained in an obstacle course, demanding significant motor coordination to complete. Control animals either traversed an obstacle-free runway or remained sedentary. Quantitative analysis of spine morphology showed that the density and length of dendritic spines along the distal dendrites of Purkinje cells were significantly increased in the rats that learned complex motor skills compared to active or inactive controls. Classification of spines into shape categories indicated that the increased spine density and length after motor learning was mainly attributable to an increase in thin spines. These findings suggest that motor learning induces structural spine plasticity in the cerebellar Purkinje neurons, which may play a crucial role in acquiring complex motor skills.     

Ultrastructural plasticity associated with hippocampal-dependent learning: a meta-analysis

In order to develop a profile of how individual synapses in the hippocampal formation alter their structure following learning experience, a meta-analysis synthesized the available literature on morphological change following hippocampal-dependent learning. Analysis of the 132 calculated effect sizes suggest a consistent profile of morphological change in the hippocampus following learning experience. Across the hippocampal formation, dendritic complexity, spine density, and the size of perforated postsynaptic densities showed consistent increases following training. Both the density of synapses in general and perforated synapses in particular showed unique responses to training, depending on the duration of training and/or different cell layers of the hippocampal formation. Most importantly, it seems that this profile, while consistent, is small and specific--only a select few of the morphological parameters typically measured in anatomical studies of plasticity showed significant change following training. Collectively, these data suggest that the distinct electrophysiological properties of neocortical versus hippocampal synapses may be at least partially mediated by distinct morphological cascades. That is, on the basis of theory, and with the support of the current data, it seems that synaptogenesis correlates with enduring neocortical plasticity, while structural changes correlate with more transient hippocampal plasticity. To be able to state these conclusions with conviction, however, more data are needed in several key areas for continued pursuit of the morphological correlates of hippocampal-dependent learning.     

Multiple subclasses of Purkinje cells in the primate floccular complex provide similar signals to guide learning in the vestibulo-ocular reflex

The neural "learning rules" governing the induction of plasticity in the cerebellum were analyzed by recording the patterns of neural activity in awake, behaving animals during stimuli that induce a form of cerebellum-dependent learning. We recorded the simple- and complex-spike responses of a broad sample of Purkinje cells in the floccular complex during a number of stimulus conditions that induce motor learning in the vestibulo-ocular reflex (VOR). Each subclass of Purkinje cells carried essentially the same information about required changes in the gain of the VOR. The correlation of simple-spike activity in Purkinje cells with activity in vestibular pathways could guide learning during low-frequency but not high-frequency stimuli. Climbing fiber activity could guide learning during all stimuli tested but only if compared with the activity present approximately 100 msec earlier in either vestibular pathways or Purkinje cells.     

Extinction as new learning versus unlearning: considerations from a computer simulation of the cerebellum

Like many forms of Pavlovian conditioning, eyelid conditioning displays robust extinction. We used a computer simulation of the cerebellum as a tool to consider the widely accepted view that extinction involves new, inhibitory learning rather than unlearning of acquisition. Previously, this simulation suggested basic mechanistic features of extinction and savings in eyelid conditioning, with predictions born out by experiments. We review previous work showing that the simulation reproduces behavioral phenomena and lesion effects generally taken as evidence that extinction does not reverse acquisition, even though its plasticity is bidirectional with no site dedicated to inhibitory learning per se. In contrast, we show that even though the sites of plasticity are, in general, affected in opposite directions by acquisition and extinction training, most synapses do not return to their naive state after acquisition followed by extinction. These results suggest caution in interpreting a range of observations as necessarily supporting extinction as unlearning or extinction as new inhibitory learning. We argue that the question “is extinction reversal of acquisition or new inhibitory learning?” is therefore not well posed because the answer may depend on factors such as the brain system in question or the level of analysis considered.Pavlovian eyelid conditioning is robustly bidirectional. Conditioned responses that are acquired via training that pairs a conditioned stimulus (CS) with an unconditioned stimulus (US) can be rapidly extinguished with CS-alone training or unpaired CS-US training (Gormezano et al. 1983; Napier et al. 1992; Macrae and Kehoe 1999; Kehoe and Macrae 2002; Kehoe and White 2002; Weidemann and Kehoe 2003). Whether extinction involves unlearning or separate inhibitory learning that suppresses conditioned response expression remains an important issue for both behavioral theories and for investigations of underlying neural mechanisms (Pavlov 1927; Hull 1943; Konorski 1948, 1967; Rescorla and Wagner 1972; Mackintosh 1974; Rescorla 1979; Bouton 1993, 2002; Falls 1998; Myers and Davis 2002; Kehoe and White 2002). Here, we addressed this issue using a computer simulation of the cerebellum that is capable of emulating many aspects of eyelid conditioning. Although simulation results cannot resolve such issues, several aspects of the simulation''s behavior are instructive. Even though the sites of plasticity are, in general, affected in opposite directions by acquisition and extinction training, the simulation can emulate several behavioral phenomena that are generally taken as evidence that extinction does not involve unlearning. Moreover, we found that the strengths of most synapses are quite different from their naive state following acquisition and then extinction. Independent of the overall biological accuracy of this simulation, these results highlight a variety of implications for ongoing debates about the roles of unlearning versus new learning in extinction.A combination of factors makes it possible to analyze the neural basis of eyelid conditioning in detail, and to build and test computer simulations of its cerebellar mechanisms (Medina and Mauk 2000). Foremost among these is the close association between eyelid conditioning and the cerebellum (Thompson 1986; Raymond et al. 1996; Mauk and Donegan 1997). Previous studies from several labs have shown that (1) cerebellar output drives the motor pathways that produce the conditioned responses (McCormick and Thompson 1984), (2) presentation of a CS is conveyed to the cerebellum via activation of certain of its mossy fiber inputs (Steinmetz et al. 1986; Hesslow et al. 1999), and (3) presentation of the US is conveyed via activation of certain climbing fiber inputs to the cerebellum (Fig. 1A; Mauk et al. 1986). These factors are complemented by the extent to which the synaptic organization and physiology of the cerebellum are known (Eccles et al. 1967; Ito 1984), as are the behavioral properties of eyelid conditioning (Gormezano et al. 1983; Kehoe and Macrae 2002). These advantages combine with the speed of current computers to make possible the construction of biologically detailed and large-scale computer simulations of the cerebellum that can then be thoroughly tested using standard eyelid conditioning protocols (Medina et al. 2000, 2001, 2002; Medina and Mauk 1999, 2000).Open in a separate windowFigure 1Emulation of eyelid conditioning in a computer simulation of the cerebellum. (A) A schematic representation of the simulation and how it was trained using an eyelid conditioning-like protocol. The output of the simulation comes from the summed activity of the six cerebellar deep nucleus cells (blue box). The CS was conveyed to the simulation by phasic activation of 18 of the 600 mossy fibers and tonic activation of six mossy fibers (green box). The US was emulated by a brief excitatory conductance applied to the single climbing fiber. The remainder of the simulation consisted of 10,000 granule cells, 900 Golgi cells, 20 stellate/basket cells, and 20 Purkinje cells with essentials of the connectivity as shown. (B) Acquisition, extinction, and savings by the simulation. Each panel shows the equivalent of 10 d of acquisition (left panel), extinction (center), and reacquisition (right) training. Individual sweeps are averages of 10 trials, which are clustered together to approximate the equivalent of one daily session of eyelid conditioning. These sessions are numbered at the left, progressing from front to back. The blue portion of the sweeps denotes the presence of the CS. (C) The strength of the mossy fiber-to-nucleus synapses in the simulation over the three phases of training. The synapses that progressively increase in strength during acquisition and reacquisition and decrease during extinction are the six that are tonically activated by the CS. Note that extinction training only slowly and thus incompletely reverses the strengthened synapses. Savings during reacquisition in the simulation is largely attributable to this residual plasticity. The continued increase in the strength of these synapses does not produce a comparable increase in response amplitude, rather, it reflects the tendency for the network to transfer plasticity from cortex (pauses in Purkinje activity produced by LTD) to the nucleus (increased strength of mossy fiber-to-nucleus synapses). How long this process continues depends on a number of unknown factors.The present results are more easily appreciated with a brief review of previous studies (Medina et al. 2000, 2001, 2002) showing how the simulation emulates acquisition, extinction, and savings during reacquisition. These phenomena are shown for the simulation in the three panels of Figure 1B. The underlying essential elements can be summarized briefly. Presentation of a CS activates subsets of granule cells, and these subsets change somewhat over the duration of the CS. Paired training induces long-term depression (LTD) at CS-activated granule-to-Purkinje synapses that are activated when the US is presented. This leads to a learned and well timed decrease in the activity of Purkinje cells during the CS (Hesslow and Ivarsson 1994), which leads to the induction of long-term potentiation (LTP) at mossy fiber-to-nucleus synapses activated by the CS. As this plasticity develops, nucleus cells encounter during the CS strong excitation combined with release from inhibition and therefore discharge robustly, thereby driving the expression of conditioned responses (McCormick and Thompson 1984). These steps suggest that learning first occurs in the cerebellar cortex, before robust conditioned responses are seen. We have observed evidence for this latent learning in cerebellar cortex (Ohyama and Mauk 2001).During extinction, CS-activated granule-to-Purkinje synapses undergo LTP because their activation occurs in the absence of climbing fiber activity. The essential suppression of climbing fiber activity below the typical level of 1 Hz is produced by inhibition from cerebellar output (Sears and Steinmetz 1991; Hesslow and Ivarsson 1996; Kenyon et al. 1998a,b; Miall et al. 1998), which is robust during the expression of conditioned responses. This prediction of the simulation is supported by observations that blocking inhibition of climbing fibers prevents extinction (Medina et al. 2002).We have shown previously that savings during reacquisition results, at least in part, from plasticity in the cerebellar deep nucleus that is relatively resistant to extinction (Medina et al. 2001). The strengths of the CS-activated mossy fiber-to-nucleus synapses in the simulation are shown in Figure 1C for acquisition, extinction, and reacquisition. Because learned pauses in Purkinje cell activity are still present early in extinction training, the strengths of CS-activated mossy fiber-to-nucleus synapses continue to increase. Once conditioned responses are fully extinguished, due to the restoration of robust Purkinje cell activity during the CS via the induction of LTP at CS-activated granule-to-Purkinje synapses, then CS-activated mossy fiber-to-nucleus synapses begin to undergo LTD and decrease in strength. The rate at which these synapses decrease in strength with additional extinction training depends on unknown factors such as the level of Purkinje activity required for induction of LTD. These results show in principle, however, that plasticity in the cerebellar cortex is sufficient to extinguish conditioned responses, and that a network displaying fully extinguished conditioned responses can still contain strengthened mossy fiber-to-nucleus synapses. In the simulation, savings occur largely because this residual plasticity in the cerebellar nucleus enhances the conditioned responses produced by the relearning of decreased activity in the Purkinje cells. In support, we have shown in rabbits that plasticity in the cerebellar nucleus persists following extinction, and that a measure of the magnitude of this residual plasticity correlates with the rate of reacquisition (Medina et al. 2001).Here, we used the mechanisms of extinction in this simulation to stimulate discussion regarding the issue of extinction as unlearning versus extinction as new learning.     

Stimulus generalization of conditioned eyelid responses produced without cerebellar cortex: implications for plasticity in the cerebellar nuclei

In Pavlovian eyelid conditioning and adaptation of the vestibulo-ocular reflex, cerebellar cortex lesions fail to completely abolish previously acquired learning, indicating an additional site of plasticity in the deep cerebellar or vestibular nucleus. Three forms of plasticity are known to occur in the deep cerebellar nuclei: formation of new synapses, plasticity at existing synapses, and changes in intrinsic excitability. Only a cell-wide increase in excitability predicts that learning should generalize broadly from a training stimulus to other stimuli capable of supporting learning, whereas the alternatives predict that learning should be relatively specific to the training stimulus. Here we show that deep nucleus plasticity, as assessed by conditioned eyelid responses produced without input from the cerebellar cortex, is relatively specific to the training conditioned stimulus (CS). We trained rabbits to a tone or light CS with periorbital stimulation as the unconditioned stimulus (US), and pharmacologically disconnected the cerebellar cortex during a posttraining generalization test. The short-latency conditioned responses unmasked by this treatment showed strong decrement along the dimension of auditory frequency and did not generalize across stimulus modalities. These results cannot be explained solely by a cell-wide increase in the excitability of deep nucleus neurons, and imply that an input-specific mechanism in the deep cerebellar nucleus operates as well.     

Memory Maintenance

ABSTRACT— Change in the synaptic communication between neurons—known as synaptic plasticity—plays a key role in learning and memory. It is not yet clear, however, whether the properties of synaptic plasticity are sufficient to account for long-term-memory maintenance. Recent studies have revealed that synaptic plasticity can indeed persist for weeks or months, as might be expected of a long-term-memory mechanism. However, memories encoded by neural systems are not static; they continue to evolve as new learning occurs. Furthermore, neural-network modeling has shown that synapses must be able to reconfigure their connection strengths during new learning if old information is to be preserved. Recent tests confirm that synapses, once modified, retain their capacity for further modification, indicating that they can indeed operate in the manner predicted to be necessary for memory maintenance in a dynamic learning network.     

Synaptic plasticity and translation initiation

It is widely accepted that protein synthesis, including local protein synthesis at synapses, is required for several forms of synaptic plasticity. Local protein synthesis enables synapses to control synaptic strength independent of the cell body via rapid protein production from pre-existing mRNA. Therefore, regulation of translation initiation is likely to be intimately involved in modulating synaptic strength. Our understanding of the translation-initiation process has expanded greatly in recent years. In this review, we discuss various aspects of translation initiation, as well as signaling pathways that might be involved in coupling neurotransmitter and neurotrophin receptors to the translation machinery during various forms of synaptic plasticity.     

Selective Synaptic Plasticity within the Cerebellar Cortex Following Complex Motor Skill Learning

Complex motor skill learning, but not mere motor activity, leads to an increase in synapse number within the cerebellar cortex. The present experiment used quantitative electron microscopy to determine which synapse types were altered in number. Adult female rats were allocated to either an acrobatic condition (AC), a voluntary exercise condition (VX), or an inactive condition (IC). AC animals were trained to traverse an elevated obstacle course requiring substantial motor coordination to complete. VX animals were housed with unlimited access to running wheels and IC animals received no motor training but were handled briefly each day. Results showed the AC animals to have significantly more parallel fiber to Purkinje cell synapses than both the VX and IC animals. No other synapse type was significantly altered. Thus, the learning-dependent increase in synapse number observed within the cerebellar cortex is accomplished primarily through the addition of parallel fiber synapses.     

From acquisition to consolidation: on the role of brain-derived neurotrophic factor signaling in hippocampal-dependent learning

One of the most rigorously investigated problems in modern neuroscience is to decipher the mechanisms by which experience-induced changes in the central nervous system are translated into behavioral acquisition, consolidation, retention, and subsequent recall of information. Brain-derived neurotrophic factor (BDNF) has recently emerged as one of the most potent molecular mediators of not only central synaptic plasticity, but also behavioral interactions between an organism and its environment. Recent experimental evidence indicates that BDNF modulates synaptic transmission and plasticity by acting across different spatial and temporal domains. BDNF signaling evokes both short- and long-term periods of enhanced synaptic physiology in both pre- and postsynaptic compartments of central synapses. Specifically, BDNF/TrkB signaling converges on the MAP kinase pathway to enhance excitatory synaptic transmission in vivo, as well as hippocampal-dependent learning in behaving animals. Emerging concepts of the intracellular signaling cascades involved in synaptic plasticity induced through environmental interactions resulting in behavioral learning further support the contention that BDNF/TrkB signaling plays a fundamental role in mediating enduring changes in central synaptic structure and function. Here we review recent literature showing the involvement of BDNF/TrkB signaling in hippocampal-dependent learning paradigms, as well as in the types of cellular plasticity proposed to underlie learning and memory.     

Cerebellar learning in the vestibulo-ocular reflex

The vestibulo-ocular reflex, because of its close relationship with the cerebellum and its marked adaptiveness, has become a model system for studying the functions of the cerebellum. It has been hypothesized that an evolutionarily old part of the cerebellum, the flocculus, forms a modifiable accessory pathway for the vestibulo-ocular reflex arc for adaptive control, and that the modification is due to the synaptic plasticity induced by retinal errors conveyed by a unique structure of the cerebellum, the climbing fibers. The flocculus hypothesis has been supported by several lines of evidence, including lesioning or functionally impairing the flocculus and recording the activity of flocculus Purkinje cells, and, more recently, from pharmacologically or genetically inhibited synaptic plasticity, which produces long-term depression. There has also been debate on a possible site for memory retention in vestibulo-ocular-reflex adaptation, and about the signal content in flocculus Purkinje cells. This article reviews recent studies on the learning mechanisms of the cerebellum that underlie the adaptation of the vestibulo-ocular reflex.     

The characteristics of LTP induced in hippocampal slices are dependent on slice-recovery conditions

In area CA1 of hippocampal slices which are allowed to recover from slicing "in interface" and where recordings are carried out in interface, a single 1-sec train of 100-Hz stimulation triggers a short-lasting long-term potentiation (S-LTP), which lasts 1-2 h, whereas multiple 1-sec trains induce a long-lasting LTP (L-LTP), which lasts several hours. Moreover, the threshold and the features of these LTP depend on the history of the neurons, a phenomenon known as metaplasticity. Here, where all recordings were performed in interface, we found that allowing the slices to recover "in submersion" had dramatic metaplastic effects. In these conditions, a single 1-sec train at 100 Hz induced an L-LTP which lasted at least 4 h and was dependent on protein synthesis. Interestingly, this type of metaplasticity was observed when the concentration of Mg(++) used was 1.0 mM but not when it was 1.3 mM. The LTP induced by four 1-sec trains at 100 Hz was similar whatever the incubation method. However, the signaling cascades recruited to achieve that pattern were different. In the interface-interface paradigm (recovery and recording both in interface) the four-train induced LTP recruited the PKA signaling pathway but not that of the p42/44MAPK. On the contrary, in the submersion-interface paradigm the four-train induced LTP recruited the p42/44MAPK signaling pathway but not that of the PKA. To our knowledge this is the first example of metaplasticity involving the recruitment of signaling cascades in LTP.     

Synaptic tagging, evaluation of memories, and the distal reward problem

Long-term synaptic plasticity exhibits distinct phases. The synaptic tagging hypothesis suggests an early phase in which synapses are prepared, or "tagged," for protein capture, and a late phase in which those proteins are integrated into the synapses to achieve memory consolidation. The synapse specificity of the tags is consistent with conventional neural network models of associative memory. Memory consolidation through protein synthesis, however, is neuron specific, and its functional role in those models has not been assessed. Here, using a theoretical network model, we test the tagging hypothesis on its potential to prolong memory lifetimes in an online-learning paradigm. We find that protein synthesis, though not synapse specific, prolongs memory lifetimes if it is used to evaluate memory items on a cellular level. In our model we assume that only "important" memory items evoke protein synthesis such that these become more stable than "unimportant" items, which do not evoke protein synthesis. The network model comprises an equilibrium distribution of synaptic states that is very susceptible to the storage of new items: Most synapses are in a state in which they are plastic and can be changed easily, whereas only those synapses that are essential for the retrieval of the important memory items are in the stable late phase. The model can solve the distal reward problem, where the initial exposure of a memory item and its evaluation are temporally separated. Synaptic tagging hence provides a viable mechanism to consolidate and evaluate memories on a synaptic basis.     

The neural cell adhesion molecule-derived peptide FGL facilitates long-term plasticity in the dentate gyrus in vivo

The neural cell adhesion molecule (NCAM) is known to play a role in developmental and structural processes but also in synaptic plasticity and memory of the adult animal. Recently, FGL, a NCAM mimetic peptide that binds to the Fibroblast Growth Factor Receptor 1 (FGFR-1), has been shown to have a beneficial impact on normal memory functioning, as well as to rescue some pathological cognitive impairments. Whether its facilitating impact may be mediated through promoting neuronal plasticity is not known. The present study was therefore designed to test whether FGL modulates the induction and maintenance of synaptic plasticity in the dentate gyrus (DG) in vivo. For this, we first assessed the effect of the FGL peptide on synaptic functions at perforant path-dentate gyrus synapses in the anesthetized rat. FGL, or its control inactive peptide, was injected locally 60 min before applying high-frequency stimulation (HFS) to the medial perforant path. The results suggest that although FGL did not alter basal synaptic transmission, it facilitated both the induction and maintenance of LTP. Interestingly, FGL also modified the heterosynaptic plasticity observed at the neighboring lateral perforant path synapses. The second series of experiments, using FGL intracerebroventricular infusion in the awake animal, confirmed its facilitating effect on LTP for up to 24 h. Our data also suggest that FGL could alter neurogenesis associated with LTP. In sum, these results show for the first time that enhancing NCAM functions by mimicking its heterophilic interaction with FGFR facilitates hippocampal synaptic plasticity in the awake, freely moving animal.     

Whereas short-term facilitation is presynaptic, intermediate-term facilitation involves both presynaptic and postsynaptic protein kinases and protein synthesis

Whereas short-term plasticity involves covalent modifications that are generally restricted to either presynaptic or postsynaptic structures, long-term plasticity involves the growth of new synapses, which by its nature involves both pre- and postsynaptic alterations. In addition, an intermediate-term stage of plasticity has been identified that might form a bridge between short- and long-term plasticity. Consistent with that idea, although short-term term behavioral sensitization in Aplysia involves presynaptic mechanisms, intermediate-term sensitization involves both pre- and postsynaptic mechanisms. However, it has not been known whether that is also true of facilitation in vitro, where a more detailed analysis of the mechanisms involved in the different stages and their interrelations is feasible. To address those questions, we have examined pre- and postsynaptic mechanisms of short- and intermediate-term facilitation at Aplysia sensory-motor neuron synapses in isolated cell culture. Whereas short-term facilitation by 1-min 5-HT involves presynaptic PKA and CamKII, intermediate-term facilitation by 10-min 5-HT involves presynaptic PKC and postsynaptic Ca(2+) and CamKII, as well as both pre- and postsynaptic protein synthesis. These results support the idea that the intermediate-term stage is the first to involve both pre- and postsynaptic molecular mechanisms, which could in turn serve as some of the initial steps in a cascade leading to synaptic growth during long-term plasticity.     

A role for ERK MAP kinase in physiologic temporal integration in hippocampal area CA1

Recent studies demonstrate a requirement for the Extracellular signal Regulated Kinase (ERK) mitogen-activated protein kinase (MAPK) cascade in both the induction of long-lasting forms of hippocampal synaptic plasticity and in hippocampus-dependent associative and spatial learning. In the present studies, we investigated mechanisms by which ERK might contribute to synaptic plasticity at Schaffer collateral synapses in hippocampal slices. We found that long-term potentiation (LTP) induced with a pair of 100-Hz tetani does not require ERK activation in mice whereas it does in rats. However, in mice, inhibition of ERK activation blocked LTP induced by two LTP induction paradigms that mimicked the endogenous θ rhythm. In an additional series of studies, we found that mice specifically deficient in the ERK1 isoform of MAPK showed no impairments in tests of hippocampal physiology. To investigate ERK-dependent mechanisms operating during LTP-inducing stimulation paradigms, we monitored spike production in the cell body layer of the hippocampus during the period of θ-like LTP-inducing stimulation. θ-burst stimulation (TBS) produced a significant amount of postsynaptic spiking, and the likelihood of spike production increased progressively over the course of the three trains of TBS independent of any apparent increase in Excitatory Post-Synaptic Potential (EPSP) magnitude. Inhibition of ERK activation dampened this TBS-associated increase in spiking. These data indicate that, for specific patterns of stimulation, ERK may function in the regulation of neuronal excitability in hippocampal area CA1. Overall, our data indicate that the progressive increase in spiking observed during TBS represents a form of physiologic temporal integration that is dependent on ERK MAPK activity.