The expression of long-term potentiation: reconciling the preists and the postivists

Long-term potentiation (LTP) of excitatory synaptic transmission in the hippocampus has been investigated in great detail over the past 40 years. Where and how LTP is actually expressed, however, remain controversial issues. Considerable evidence has been offered to support both pre- and postsynaptic contributions to LTP expression. Though it is widely held that postsynaptic expression mechanisms are the primary contributors to LTP expression, evidence for that conclusion is amenable to alternative explanations. Here, we briefly review some key contributions to the ‘locus’ debate and describe data that support a dominant role for presynaptic mechanisms. Recognition of the state-dependency of expression mechanisms, and consideration of the consequences of the spatial relationship between postsynaptic glutamate receptors and presynaptic vesicular release sites, lead to a model that may reconcile views from both sides of the synapse.     

Structural changes at dendritic spine synapses during long-term potentiation

Two key hypotheses about the structural basis of long-term potentiation (LTP) are evaluated in light of new findings from immature rat hippocampal slices. First, it is shown why dendritic spines do not split during LTP. Instead a small number of spine-like dendritic protrusions may emerge to enhance connectivity with potentiated axons. These 'same dendrite multiple synapse boutons' provide less than a 3% increase in connectivity and do not account for all of LTP or memory, as they do not accumulate during maturation. Second, polyribosomes in dendritic spines served to identify which of the existing synapses enlarged to sustain more than a 30% increase in synaptic strength. Thus, both enhanced connectivity and enlarged synapses result during LTP, with synapse enlargement being the greater effect.     

Activity-dependent changes of the hippocampal CA3–CA1 synapse during the acquisition of associative learning in conscious mice

Contemporary neuroscientists are paying increasing attention to subcellular, molecular and electrophysiological mechanisms underlying learning and memory processes. Recent efforts have addressed the development of transgenic mice affected at different stages of the learning process, or emulating pathological conditions involving cognition and motor-learning capabilities. However, a parallel effort is needed to develop stimulating and recording techniques suitable for use in behaving mice, in order to grasp activity-dependent neural changes taking place during the very moment of the process. These in vivo models should integrate the fragmentary information collected by different molecular and in vitro approaches. In this regard, long-term potentiation (LTP) has been proposed as the neural mechanism underlying synaptic plasticity. Moreover, N -methyl- d -aspartate (NMDA) receptors are accepted as the molecular substrate of LTP. It now seems necessary to study the relationship of both LTP and NMDA receptors with the plastic changes taking place, in selected neural structures, during actual learning. Here, we review data on the involvement of the hippocampal CA3–CA1 synapse in the acquisition of classically conditioned eyelid conditioned responses (CRs) in behaving mice. Available data show that LTP, evoked by high-frequency stimulation of Schaffer collaterals, disturbs both the acquisition of CRs and the physiological changes that occur at the CA3–CA1 synapse during learning. Moreover, the administration of NMDA-receptor antagonists is able not only to prevent LTP induction in vivo , but also to hinder the formation of both CRs and functional changes in strength of the CA3–CA1 synapse. Thus, there is experimental evidence relating activity-dependent synaptic changes taking place during actual learning with LTP mechanisms and with the role of NMDA receptors in both processes.     

Computational model of the effects of stochastic conditioning on the induction of long-term potentiation and depression

The long-term potentiation (LTP) or long-term depression (LTD) of synaptic strength are currently considered to be the first microscopic steps leading to learning and memory. The great majority of experiments (both in vitro and in vivo) studying the basic mechanisms of LTP and LTD induction use conditioning protocols in which the presynaptic stimuli are delivered at constant frequencies. This is not, however, what is commonly found in vivo, where a highly irregular spiking activity seems to drive most of the neuronal functions. Thus, some important aspects of the induction characteristics of LTP and LTD expressed in vivo might have been overlooked by the experiments. Using a simple schematic model for a synapse we show here that, in fact, the statistical properties of a presynaptic conditioning signal could change the probability to induce LTP and/or LTD, suggesting a new and faster operating mode for a synapse. Received: 3 September 1998 / Accepted in revised form: 14 April 1999     

Curcumin Rescues Aging-Related Loss of Hippocampal Synapse Input Specificity of Long Term Potentiation in Mice

Curcumin has neuroprotective effect and could enhance memory. However, the mechanisms underlying the protection of curcumin on aging-related memory decline are not well understood. In this study, high frequency stimulation (HFS)-induced long term potentiation (LTP) was evaluated by a cellular model of memory formation. A two-input stimulation paradigm was used to record the potentiation as well as synapse input specificity. The data suggested that an N-Methyl-d-aspartate receptors (NMDAR) -dependent LTP was inducible in adult hippocampal slices with a characteristic of synapse input specificity. It also indicated that aging resulted in a reduction in LTP but more importantly a loss of synaptic input specificity. The reason behind the above conclusions is that LTP induction is more dependent on the calcium channel. This is due to a switch of the dependence of LTP induction to voltage-dependent calcium channel (VDCC) compared to NMDA receptors. Curcumin administration recovers input specificity by re-establishing NMDA receptor dependence of induction. In addition, curcumin administration ameliorated aging-related increase of brain thiobarbituric acid-reactive substances and elevated aging-related decrease of glutathione in hippocampus. It is then concluded that curcumin modulates hippocampal redox status and restores aging-related loss of synapse input specificity of HFS-induced LTP by switching VDCC calcium source into NMDA receptor-dependent one.     

Long-term potentiation selectively expressed by NMDA receptors at hippocampal mossy fiber synapses

The mossy fiber to CA3 pyramidal cell synapse (mf-CA3) provides a major source of excitation to the hippocampus. Thus far, these glutamatergic synapses are well recognized for showing a presynaptic, NMDA receptor-independent form of LTP that is expressed as a long-lasting increase of transmitter release. Here, we show that in addition to this "classical" LTP, mf-CA3 synapses can undergo a form of LTP characterized by a selective enhancement of NMDA receptor-mediated transmission. This potentiation requires coactivation of NMDA and mGlu5 receptors and a postsynaptic calcium rise. Unlike classical LTP, expression of this mossy fiber LTP is due to a PKC-dependent recruitment of NMDA receptors specifically to the mf-CA3 synapse via a SNARE-dependent process. Having two mechanistically different forms of LTP may allow mf-CA3 synapses to respond with more flexibility to the changing demands of the hippocampal network.     

Long-term potentiation of hippocampal mossy fiber synapses is blocked by postsynaptic injection of calcium chelators

The role of intracellular calcium in an APV-insensitive form of long-term potentiation (LTP) has been studied at the hippocampal mossy fiber synapse. Intracellular calcium was buffered by iontophoretic injection of either BAPTA or QUIN-2, into CA3 pyramidal neurons. The slow calcium-dependent after hyperpolarization was used as an indicator of buffering. LTP was elicited in control and in APV-treated cells (6/6 and 4/5 cell, respectively). In contrast, LTP was observed in only 2/9 BAPTA-loaded cells and in 1/4 QUIN-2-loaded cells. The magnitude of LTP for control and APV-treated cells were not significantly different, but both groups showed significantly greater LTP than BAPTA-loaded cells. These results suggest that an increase in postsynaptic calcium is required for the induction of mossy fiber LTP.     

State-dependent mechanisms of LTP expression revealed by optical quantal analysis

The expression mechanism of long-term potentiation (LTP) remains controversial. Here we combine electrophysiology and Ca(2+) imaging to examine the role of silent synapses in LTP expression. Induction of LTP fails to change p(r) at these synapses but instead mediates an unmasking process that is sensitive to the inhibition of postsynaptic membrane fusion. Once unmasked, however, further potentiation of formerly silent synapses leads to an increase in p(r). The state of the synapse thus determines how LTP is expressed.     

Control of Cerebellar Long-Term Potentiation by P-Rex-Family Guanine-Nucleotide Exchange Factors and Phosphoinositide 3-Kinase

Background

Long-term potentiation (LTP) at the parallel fibre–Purkinje cell synapse in the cerebellum is a recently described and poorly characterized form of synaptic plasticity. The induction mechanism for LTP at this synapse is considered reciprocal to “classical” LTP at hippocampal CA1 pyramidal neurons: kinases promote increased trafficking of AMPA receptors into the postsynaptic density in the hippocampus, whereas phosphatases decrease internalization of AMPA receptors in the cerebellum. In the hippocampus, LTP occurs in overlapping phases, with the transition from early to late phases requiring the consolidation of initial induction processes by structural re-arrangements at the synapse. Many signalling pathways have been implicated in this process, including PI3 kinases and Rho GTPases.

Principal Findings

We hypothesized that analogous phases are present in cerebellar LTP, and took as the starting point for investigation our recent discovery that P-Rex – a Rac guanine nucleotide exchange factor which is activated by PtdIns(3,4,5)P₃ – is highly expressed in mouse cerebellar Purkinje neurons and plays a role in motor coordination. We found that LTP evoked at parallel fibre synapses by 1 Hz stimulation or by NO donors was not sustained beyond 30 min when P-Rex was eliminated or Rac inhibited, suggesting that cerebellar LTP exhibits a late phase analogous to hippocampal LTP. In contrast, inhibition of PI3 kinase activity eliminated LTP at the induction stage.

Conclusions

Our data suggest that a PI3K/P-Rex/Rac pathway is required for late phase LTP in the mouse cerebellum, and that other PI3K targets, which remain to be discovered, control LTP induction.     

Pair recordings reveal all-silent synaptic connections and the postsynaptic expression of long-term potentiation

The activation of silent synapses is a proposed mechanism to account for rapid increases in synaptic efficacy such as long-term potentiation (LTP). Using simultaneous recordings from individual pre- and postsynaptic neurons in organotypic hippocampal slices, we show that two CA3 neurons can be connected entirely by silent synapses. Increasing release probability or application of cyclothiazide does not produce responses from these silent synapses. Direct measurement of NMDAR-mediated postsynaptic responses in all-silent synaptic connections before and after LTP induction show no change in failure rate, amplitude, or area. These data do not support hypotheses that synapse silent results from presynaptic factors or that LTP results from increases in presynaptic glutamate release. LTP is also associated with an increase in postsynaptic responsiveness to exogenous AMPA. We conclude that synapse silence, activation, and expression of LTP are postsynaptic.     

Increasing numbers of synaptic puncta during late-phase LTP: N-cadherin is synthesized, recruited to synaptic sites, and required for potentiation

It is an open question whether new synapses form during hippocampal LTP. Here, we show that late-phase LTP (L-LTP) is associated with a significant increase in numbers of synaptic puncta identified by synaptophysin and N-cadherin, an adhesion protein involved in synapse formation during development. During potentiation, protein levels of N-cadherin are significantly elevated and N-cadherin dimerization is enhanced. The increases in synaptic number and N-cadherin levels are dependent on cAMP-dependent protein kinase (PKA) and protein synthesis, both of which are also required for L-LTP. Blocking N-cadherin adhesion prevents the induction of L-LTP, but not the early-phase of LTP (E-LTP). Our data suggest that N-cadherin is synthesized during the induction of L-LTP and recruited to newly forming synapses. N-cadherin may play a critical role in L-LTP by holding nascent pre-and postsynaptic membranes in apposition, enabling incipient synapses to acquire function and contribute to potentiation.     

Actin's actions in LTP-induced synapse growth

F-actin is required for LTP induction, but the underlying mechanisms are unclear. New results show that LTP produces an increase in actin-rich spines. Furthermore, these spines have large synapses, strongly suggesting that LTP involves synapse growth. This process appears to require LIMK-1 phosphorylation of the actin depolymerizing factor cofilin.     

An in vitro study of long-term potentiation in the carp (Cyprinus carpio L.) olfactory bulb

Long-term potentiation (LTP) of synaptic transmission is considered a cellular mechanism for neural plasticity and memory formation. Previously, we showed that in the carp olfactory bulb, LTP occurs at the dendrodendritic mitral-to-granule cell synapse following tetanic electrical stimulation applied to the olfactory tract, and suggested that it is involved in the process of olfactory memory formation. As a first step towards understanding mechanisms underlying plasticity at this synapse, we examined the effects of various drugs (glutamate and GABA receptor agonists and antagonists, noradrenaline, and drugs affecting cAMP signaling) on dendrodendritic mitral-to-granule cell synaptic transmission in an in vitro preparation. Two forms of LTP are involved: a postsynaptic form (tetanus-evoked LTP) and a presynaptic form. The postsynaptic form is evoked at the granule cell dendrite following tetanic olfactory tract stimulation and is suppressed by the NMDA receptor antagonist, D-AP5, enhanced by noradrenaline, and occluded by the metabotropic glutamate receptor agonist, trans-ACPD. The presynaptic form occurs at the mitral cell dendrite following blockade of the GABA_A receptor by picrotoxin and bicuculline, or via activation of cAMP signaling by forskolin and 8-Br-cAMP.     

Distinct roles for ephrinB3 in the formation and function of hippocampal synapses

The transmembrane ephrinB ligands and their Eph receptor tyrosine kinases are known to regulate excitatory synaptic functions in the hippocampus. In the CA3-CA1 synapse, ephrinB ligands are localized to the post-synaptic membrane, while their cognate Eph receptors are presumed to be pre-synaptic. Interaction of ephrinB molecules with Eph receptors leads to changes in long-term potentiation (LTP), which has been reported to be mediated by reverse signaling into the post-synaptic membrane. Here, we demonstrate that the cytoplasmic domain of ephrinB3 and hence reverse signaling is not required for ephrinB dependent learning and memory tasks or for LTP of these synapses. Consistent with previous reports, we find that ephrinB3(KO) null mutant mice exhibit a striking reduction in CA3-CA1 LTP that is associated with defective learning and memory tasks. We find the null mutants also show changes in both pre- and post-synaptic proteins including increased levels of synapsin and synaptobrevin and reduced levels of NMDA receptor subunits. These abnormalities are not observed in ephrinB3(lacZ) reverse signaling mutants that specifically delete the ephrinB3 intracellular region, supporting a cytoplasmic domain-independent forward signaling role for ephrinB3 in these processes. We also find that both ephrinB3(KO) and ephrinB3(lacZ) mice show an increased number of excitatory synapses, demonstrating a cytoplasmic-dependent reverse signaling role of ephrinB3 in regulating synapse number. Together, these data suggest that ephrinB3 may act like a receptor to transduce reverse signals to regulate the number of synapses formed in the hippocampus, and that it likely acts to stimulate forward signaling to modulate a number of other proteins involved in synaptic activity and learning/memory.     

Long-term potentiation of AMPA- and NMDA-components of minimal postsynaptic currents in CA1 area of the rat hippocampus]

Excitatory postsynaptic currents (EPSC) were recorded from pyramidal neurons of the rat hippocampal slices as well as the AMPA and NMDA components. A strong enough correlation between the amplitudes of the components provided a reliable evidence of their generation by the same synapse. Both components revealed similar LTP following afferent tetanisation. The data obtained do not support postsynaptic mechanisms of the LTP maintenance but suggest that increased presynaptic release represents a basic mechanism of the early LTP maintenance.     

Vasopressin Inhibits LTP in the CA2 Mouse Hippocampal Area

Growing evidence points to vasopressin (AVP) as a social behavior regulator modulating various memory processes and involved in pathologies such as mood disorders, anxiety and depression. Accordingly, AVP antagonists are actually envisaged as putative treatments. However, the underlying mechanisms are poorly characterized, in particular the influence of AVP on cellular or synaptic activities in limbic brain areas involved in social behavior. In the present study, we investigated AVP action on the synapse between the entorhinal cortex and CA2 hippocampal pyramidal neurons, by using both field potential and whole-cell recordings in mice brain acute slices. Short application (1 min) of AVP transiently reduced the synaptic response, only following induction of long-term potentiation (LTP) by high frequency stimulation (HFS) of afferent fibers. The basal synaptic response, measured in the absence of HFS, was not affected. The Schaffer collateral-CA1 synapse was not affected by AVP, even after LTP, while the Schaffer collateral-CA2 synapse was inhibited. Although investigated only recently, this CA2 hippocampal area appears to have a distinctive circuitry and a peculiar role in controlling episodic memory. Accordingly, AVP action on LTP-increased synaptic responses in this limbic structure may contribute to the role of this neuropeptide in controlling memory and social behavior.     

Hippocampal neurons recycle BDNF for activity-dependent secretion and LTP maintenance

Regulation of brain-derived neurotrophic factor (BDNF) secretion plays a critical role in long-term potentiation (LTP). It is generally thought that the supply for this secretion is newly synthesized BDNF targeted to the synapse. Here we provide evidence that hippocampal neurons additionally recycle BDNF for activity-dependent secretion. Exogenously applied BDNF is internalized by cultured neurons and rapidly becomes available for activity-dependent secretion, which is controlled by the same mechanisms that regulate the secretion of newly synthesized BDNF. Moreover, BDNF recycling replaced the new synthesis pathway in mediating the maintenance of LTP in hippocampal slices: the late phase LTP, which is abolished by protein synthesis inhibition, was rescued in slices preincubated with BDNF. Thus, endocytosed BDNF is fed back to the activity-dependent releasable pool required for LTP maintenance.     

Long-term potentiation and depression induced by a stochastic conditioning of a model synapse.

Protracted presynaptic activity can induce long-term potentiation (LTP) or long-term depression (LTD) of the synaptic strength. However, virtually all the experiments testing how LTP and LTD depend on the conditioning input are carried out with trains of stimuli at constant frequencies, whereas neurons in vivo most likely experience a stochastic variation of interstimulus intervals. We used a computational model of synaptic transmission to test if and to what extent the stochastic fluctuations of an input signal could alter the probability to change the state of a synapse. We found that, even if the mean stimulation frequency was maintained constant, the probability to induce LTD and LTP could be a function of the temporal variation of the input activity. This mechanism, which depends only on the statistical properties of the input and not on the onset of additional biochemical mechanisms, is not usually considered in the experiments, but it could have an important role to determine the amount of LTP/LTD induction in vivo. In response to a change in the distribution of the interstimulus intervals, as measured by the coefficient of variation, a synapse could be easily adapted to inputs that might require immediate attention, with a shift of the input thresholds required to elicit LTD or LTP, which are restored to their initial conditions as soon as the input pattern returns to the original temporal distribution.     

PKMζ Inhibition Reverses Learning-Induced Increases in Hippocampal Synaptic Strength and Memory during Trace Eyeblink Conditioning

A leading candidate in the process of memory formation is hippocampal long-term potentiation (LTP), a persistent enhancement in synaptic strength evoked by the repetitive activation of excitatory synapses, either by experimental high-frequency stimulation (HFS) or, as recently shown, during actual learning. But are the molecular mechanisms for maintaining synaptic potentiation induced by HFS and by experience the same? Protein kinase Mzeta (PKMζ), an autonomously active atypical protein kinase C isoform, plays a key role in the maintenance of LTP induced by tetanic stimulation and the storage of long-term memory. To test whether the persistent action of PKMζ is necessary for the maintenance of synaptic potentiation induced after learning, the effects of ZIP (zeta inhibitory peptide), a PKMζ inhibitor, on eyeblink-conditioned mice were studied. PKMζ inhibition in the hippocampus disrupted both the correct retrieval of conditioned responses (CRs) and the experience-dependent persistent increase in synaptic strength observed at CA3-CA1 synapses. In addition, the effects of ZIP on the same associative test were examined when tetanic LTP was induced at the hippocampal CA3-CA1 synapse before conditioning. In this case, PKMζ inhibition both reversed tetanic LTP and prevented the expected LTP-mediated deleterious effects on eyeblink conditioning. Thus, PKMζ inhibition in the CA1 area is able to reverse both the expression of trace eyeblink conditioned memories and the underlying changes in CA3-CA1 synaptic strength, as well as the anterograde effects of LTP on associative learning.     

Long-lasting potentiation of excitatory synaptic signaling to the crayfish lateral giant neuron

The neural circuit that underlies the lateral giant fiber (LG)-mediated reflex escape in crayfish has provided findings relating synaptic change to nonassociative learning such as sensitization and habituation. The LGs receive sensory inputs from the primary sensory afferents and a group of mechanosensory interneurons (MSIs). An increase of excitability by suprathreshold repetitive excitation of this circuit, which is similar to Hebbian long-term potentiation (LTP), has been reported [Miller et al. (1987) J Neurosci 7:1081]. This potentiation was previously thought to result from the enhancement of transmission at cholinergic synapses between primary afferents and MSIs but not the electrical synapses onto LG. In this study, we found that potentiation of synaptic signaling at the electrical synapse onto LG can also be induced when the synapse was activated with subthreshold repetitive pulses or with a few strong suprathreshold shocks. LG LTP was induced in the preparation which had received pulses at limited frequency range. Although whether this LTP is involved in the learning process of escape behavior in crayfish is not clear, the intensity and amount of sensory stimulation used here mimicked those that could easily be produced by a predator trying to catch a crayfish and could be of adaptive significance in life.