Interplay of the magnitude and time-course of postsynaptic Ca<Superscript>2 + </Superscript> concentration in producing spike timing-dependent plasticity

Synaptic strength can be modified by the relative timing of pre- and postsynaptic activity, a phenomenon termed spike timing-dependent plasticity (STDP). Studies of neurons in the hippocampus and in other regions have found that when presynaptic activity occurs within a narrow time window, typically 10 or 20 ms, before postsynaptic activity, long-term potentiation (LTP) is induced, while if presynaptic activity occurs within a similar time window after postsynaptic activity, long-term depression (LTD) results. The mechanisms underlying these modifications are not completely understood, although there is strong evidence that the postsynaptic Ca ^2 + concentration plays a central role. Some previous modeling of STDP has focused on the dynamics of the postsynaptic Ca ^2 + concentration, while other work has studied biophysical mechanisms of how a synapse can exist in, and switch between, different states corresponding to LTP and LTD. Building on previous work in these two areas we have developed the first low level STDP model of a tristable biochemical system that incorporates induction and maintenance of both LTP and LTD. Our model is able to explain the STDP observed in hippocampal neurons in response to pre- and postsynaptic pulse pairs, using only parameters derived from previous work and without the need for parameter fine-tuning. Our results also give insight into how and why the time course of the postsynaptic Ca ^2 + concentration can lead to either LTP or LTD, and suggest that voltage dependent calcium channels play a key role.     

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.     

Presynaptic LTP and LTD of Excitatory and Inhibitory Synapses

Ubiquitous forms of long-term potentiation (LTP) and depression (LTD) are caused by enduring increases or decreases in neurotransmitter release. Such forms or presynaptic plasticity are equally observed at excitatory and inhibitory synapses and the list of locations expressing presynaptic LTP and LTD continues to grow. In addition to the mechanistically distinct forms of postsynaptic plasticity, presynaptic plasticity offers a powerful means to modify neural circuits. A wide range of induction mechanisms has been identified, some of which occur entirely in the presynaptic terminal, whereas others require retrograde signaling from the postsynaptic to presynaptic terminals. In spite of this diversity of induction mechanisms, some common induction rules can be identified across synapses. Although the precise molecular mechanism underlying long-term changes in transmitter release in most cases remains unclear, increasing evidence indicates that presynaptic LTP and LTD can occur in vivo and likely mediate some forms of learning.At several excitatory and inhibitory synapses, neuronal activity can trigger enduring increases or decreases in neurotransmitter release, thereby producing long-term potentiation (LTP) or long-term depression (LTD) of synaptic strength, respectively. In the last decade, many studies have revealed that these forms of plasticity are ubiquitously expressed in the mammalian brain, and accumulating evidence indicates that they may underlie behavioral adaptations occurring in vivo. These studies have also uncovered a wide range of induction mechanisms, which converge on the presynaptic terminal where an enduring modification in the neurotransmitter release process takes place. Interestingly, presynaptic forms of LTP/LTD can coexist with classical forms of postsynaptic plasticity. Such diversity expands the dynamic range and repertoire by which neurons modify their synaptic connections. This review discusses mechanistic aspects of presynaptic LTP and LTD at both excitatory and inhibitory synapses in the mammalian brain, with an emphasis on recent findings.     

Effect of the Initial Synaptic State on the Probability to Induce Long-Term Potentiation and Depression

Long-term potentiation (LTP) and long-term depression (LTD) are the two major forms of long-lasting synaptic plasticity in the mammalian neurons, and are directly related to higher brain functions such as learning and memory. Experimentally, they are characterized by a change in the strength of a synaptic connection induced by repetitive and properly patterned stimulation protocols. Although many important details of the molecular events leading to LTP and LTD are known, experimenters often report problems in using standard induction protocols to obtain consistent results, especially for LTD in vivo. We hypothesize that a possible source of confusion in interpreting the results, from any given experiment on synaptic plasticity, can be the intrinsic limitation of the experimental techniques, which cannot take into account the actual state and peak conductance of the synapses before the conditioning protocol. In this article, we investigate the possibility that the same experimental protocol may result in different consequences (e.g., LTD instead of LTP), according to the initial conditions of the stimulated synapses, and can generate confusing results. Using biophysical models of synaptic plasticity and hippocampal CA1 pyramidal neurons, we study how, why, and to what extent the phenomena observed at the soma after induction of LTP/LTD reflects the actual (local) synaptic state. The model and the results suggest a physiologically plausible explanation for why LTD induction is experimentally difficult to obtain. They also suggest experimentally testable predictions on the stimulation protocols that may be more effective.     

Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors

There is a consensus that NMDA receptors (NMDARs) detect coincident pre- and postsynaptic activity during induction of long-term potentiation (LTP), but their role in timing-dependent long-term depression (tLTD) is unclear. We examine tLTD in neocortical layer 5 (L5) pyramidal pairs and find that tLTD is expressed presynaptically, implying retrograde signaling. CB1 agonists produce depression that mimics and occludes tLTD. This agonist-induced LTD requires presynaptic activity and NMDAR activation, but not postsynaptic Ca(2+) influx. Further experiments demonstrate the existence of presynaptic NMDARs that underlie the presynaptic activity dependence. Finally, manipulating cannabinoid breakdown alters the temporal window for tLTD. In conclusion, tLTD requires simultaneous activation of presynaptic NMDA and CB1 receptors. This novel form of coincidence detection may explain the temporal window of tLTD and may also impart synapse specificity to cannabinoid retrograde signaling.     

Postsynaptic calcium and calcium-dependent processes in synaptic plasticity in the developing visual cortex

In this paper we describe some of the results obtained from recent experiments on mechanisms underlying long-term potentiation (LTP) and long-term depression (LTD) in the visual cortex of young rats. In particular, we focus on experiments which tested the hypotheses that the induction of LTP in the visual cortex is of Hebbian type and that an input-associated Ca²⁺ rise at postsynaptic sites and subsequent activation of protein kinases or protein phosphatases may play roles in the induction of LTP or LTD in the developing visual cortex.     

钙依赖性突触的可塑性

突触前和突触后细胞内钙离子（[Ca^2 ]i)在短时程和长时程突触的可塑性中,发挥着重要的住处传递作用。兴奋后残留[Ca^2 ]i,可以激发短时程突触增强。突触前[Ca^2 ]i可以影响被抑制的突触前膜囊泡的更新,并准确编码突前和突触后信息,产生截然相反的长时程突触修（ＬＴＰ或ＬＴＤ）。     

Molecular constraints on synaptic tagging and maintenance of long-term potentiation: a predictive model

Protein synthesis-dependent, late long-term potentiation (LTP) and depression (LTD) at glutamatergic hippocampal synapses are well characterized examples of long-term synaptic plasticity. Persistent increased activity of protein kinase M ζ (PKMζ) is thought essential for maintaining LTP. Additional spatial and temporal features that govern LTP and LTD induction are embodied in the synaptic tagging and capture (STC) and cross capture hypotheses. Only synapses that have been "tagged" by a stimulus sufficient for LTP and learning can "capture" PKMζ. A model was developed to simulate the dynamics of key molecules required for LTP and LTD. The model concisely represents relationships between tagging, capture, LTD, and LTP maintenance. The model successfully simulated LTP maintained by persistent synaptic PKMζ, STC, LTD, and cross capture, and makes testable predictions concerning the dynamics of PKMζ. The maintenance of LTP, and consequently of at least some forms of long-term memory, is predicted to require continual positive feedback in which PKMζ enhances its own synthesis only at potentiated synapses. This feedback underlies bistability in the activity of PKMζ. Second, cross capture requires the induction of LTD to induce dendritic PKMζ synthesis, although this may require tagging of a nearby synapse for LTP. The model also simulates the effects of PKMζ inhibition, and makes additional predictions for the dynamics of CaM kinases. Experiments testing the above predictions would significantly advance the understanding of memory maintenance.     

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.     

Induction of Long-Term Depression of Synaptic Transmission in a Co-Culture of DRG and Spinal Dorsal Horn Neurons of Rats

In a co-culture of dissociated neurons of lumbar dorsal root ganglia (DRG) and spinal dorsal horn (DH) neurons of newborn rats, we examined peculiarities of induction of long-term depression (LTD) of synaptic transmission through synapses formed by primary afferents on DH neurons. Induction of LTD was provided by low-frequency (5 sec⁻¹) microstimulation of single DRG neurons. Ion currents were simultaneously recorded in pre- and post-synaptic cells using a dual whole-cell path-clamp technique. Parameters of evoked excitatory and inhibitory postsynaptic currents (eEPSCs and eIPSCs, respectively) initiated in DH neurons by intracellular stimulation of DRG neurons were analyzed. Monosynaptic eEPSC mediated by activation of AMPA receptors demonstrated no sensitivity to blockers of NMDA and kainate receptors (20 μM D_L-AP5 and 10 μM SIM 2081, respectively), but were entirely blocked upon applications of 10 μM DNQX. Monosynaptic glycinergic eIPSCs found in some of the DH neurons were blocked by 1 μM strychnine and were insensitive to 10 μM bicuculline and blockers of glutamatergic neurotransmission, D_L-AP5 and DNQX. Long-lasting (360 sec) low-frequency stimulation of DRG neurons did not affect the amplitude of glycineinduced eIPSCs in DH neurons. At the same time, such stimulation of DRG neurons evoked a drop in the amplitude of AMPA-activated eEPSCs in DH neurons to 41.6 ± 2.5%, on average, as compared with the analogous index in the control. This effect lasted at least 20 min after stimulation. Long-term depression of glutamatergic transmission in DH neurons was observed at the holding potential of −70 mV and did not change after applications of 10 μM bicuculline and 1 μM strychnine. The LTD intensity depended on the duration of low-frequency stimulation of primary afferent neurons. Sequential stimulation of DRG neurons lasting 120, 160, 200, and 240 sec resulted in decreases in the eEPSC amplitude in DH neurons to 85.6 ± 3.9, 62.7 ± 4.3, 51.8 ± 3.5, and 41.6 ±2.5% with respect to control values. Our findings show that use-dependent induction of homosynaptic LTD of glutamatergic transmission is possible at the level of a separate pair of synaptically connected DRG and DH neurons under co-culturing conditions. Such LTD of glutamatergic synaptic transmission mostly mediated by activation of AMPA receptors depends on the duration of activation of a presynaptic DRG neuron and does not need depolarization of a postsynaptic DH neuron.     

Tag-Trigger-Consolidation: A Model of Early and Late Long-Term-Potentiation and Depression

Changes in synaptic efficacies need to be long-lasting in order to serve as a substrate for memory. Experimentally, synaptic plasticity exhibits phases covering the induction of long-term potentiation and depression (LTP/LTD) during the early phase of synaptic plasticity, the setting of synaptic tags, a trigger process for protein synthesis, and a slow transition leading to synaptic consolidation during the late phase of synaptic plasticity. We present a mathematical model that describes these different phases of synaptic plasticity. The model explains a large body of experimental data on synaptic tagging and capture, cross-tagging, and the late phases of LTP and LTD. Moreover, the model accounts for the dependence of LTP and LTD induction on voltage and presynaptic stimulation frequency. The stabilization of potentiated synapses during the transition from early to late LTP occurs by protein synthesis dynamics that are shared by groups of synapses. The functional consequence of this shared process is that previously stabilized patterns of strong or weak synapses onto the same postsynaptic neuron are well protected against later changes induced by LTP/LTD protocols at individual synapses.     

Synaptic Long-Term Potentiation and Depression in the Rat Medial Vestibular Nuclei Depend on Neural Activation of Estrogenic and Androgenic Signals

Estrogenic and androgenic steroids can be synthesised in the brain and rapidly modulate synaptic transmission and plasticity through direct interaction with membrane receptors for estrogens (ERs) and androgens (ARs). We used whole cell patch clamp recordings in brainstem slices of male rats to explore the influence of ER and AR activation and local synthesis of 17β-estradiol (E2) and 5α-dihydrotestosterone (DHT) on the long-term synaptic changes induced in the neurons of the medial vestibular nucleus (MVN). Long-term depression (LTD) and long-term potentiation (LTP) caused by different patterns of high frequency stimulation (HFS) of the primary vestibular afferents were assayed under the blockade of ARs and ERs or in the presence of inhibitors for enzymes synthesizing DHT (5α-reductase) and E2 (P450-aromatase) from testosterone (T). We found that LTD is mediated by interaction of locally produced androgens with ARs and LTP by interaction of locally synthesized E2 with ERs. In fact, the AR block with flutamide prevented LTD while did not affect LTP, and the blockade of ERs with ICI 182,780 abolished LTP without influencing LTD. Moreover, the block of P450-aromatase with letrozole not only prevented the LTP induction, but inverted LTP into LTD. This LTD is likely due to the local activation of androgens, since it was abolished under blockade of ARs. Conversely, LTD was still induced in the presence of finasteride the inhibitor of 5α-reductase demonstrating that T is able to activate ARs and induce LTD even when DHT is not synthesized. This study demonstrates a key and opposite role of sex neurosteroids in the long-term synaptic changes of the MVN with a specific role of T-DHT for LTD and of E2 for LTP. Moreover, it suggests that different stimulation patterns can lead to LTD or LTP by specifically activating the enzymes involved in the synthesis of androgenic or estrogenic neurosteroids.     

Regulation of Long-Term Plasticity Induction by the Channel and C-Terminal Domains of GluN2 Subunits

Conventional long-term potentiation (LTP) and long-term depression (LTD) are induced by different patterns of synaptic stimulation, but both forms of synaptic modification require calcium influx through NMDA receptors (NMDARs). A prevailing model (the “calcium hypothesis”) suggests that high postsynaptic calcium elevation results in LTP, whereas moderate elevations give rise to LTD. Recently, additional evidence has come to suggest that differential activation of NMDAR subunits also factors in determining which type of plasticity is induced. While the growing amount of data suggest that activation of NMDARs containing specific GluN2 subunits plays an important role in the induction of plasticity, it remains less clear which subunit is tied to which form of plasticity. Additionally, it remains to be determined which properties of the subunits confer upon them the ability to differentially induce long-term plasticity. This review highlights recent studies suggesting differential roles for the subunits, as well as findings that begin to shed light on how two similar subunits may be linked to the induction of opposing forms of plasticity.     

A model for long-term potentiation and depression

A computational model of long-term potentiation (LTP) and long-term depression (LTD) in the hippocampus is presented. The model assumes the existence of retrograde signals, is in good agreement with several experimental data on LTP, LTD, and their pharmacological manipulations, and shows how a simple kinetic scheme can capture the essential characteristics of the processes involved in LTP and LTD. We propose that LTP and LTD could be two different but conceptually similar processes, induced by the same class of retrograde signals, and maintained by two distinct mechanisms. An interpretation of a number of experiments in terms of the molecular processes involved in LTP and LTD induction and maintenance, and the roles of a retrograde signal are presented and discussed.     

Direct measurement of quantal changes underlying long-term potentiation in CA1 hippocampus.

The modification responsible for the long-term synaptic potentiation (LTP) that follows a brief conditioning period is not known. To elucidate this change, we have resolved quantal levels of transmission before and after induction of LTP. We find an increase both in the number of quanta released and in quantal amplitude, consistent with combined pre- and postsynaptic modifications. On average, about 60% of LTP can be accounted for by presynaptic enhancement. The increase in either quantal amplitude or quantal content varies significantly among different experiments, but is inversely correlated with its initial value. These results may help to reconcile the different views concerning the site of LTP expression.     

G protein-coupled receptors control NMDARs and metaplasticity in the hippocampus

Long-term potentiation (LTP) and long-term depression (LTD) are the major forms of functional synaptic plasticity observed at CA1 synapses of the hippocampus. The balance between LTP and LTD or “metaplasticity” is controlled by G-protein coupled receptors (GPCRs) whose signal pathways target the N-methyl-D-asparate (NMDA) subtype of excitatory glutamate receptor. We discuss the protein kinase signal cascades stimulated by Gαq and Gαs coupled GPCRs and describe how control of NMDAR activity shifts the threshold for the induction of LTP.     

NMDA Receptor-Dependent Long-Term Potentiation and Long-Term Depression (LTP/LTD)

Long-term potentiation and long-term depression (LTP/LTD) can be elicited by activating N-methyl-d-aspartate (NMDA)-type glutamate receptors, typically by the coincident activity of pre- and postsynaptic neurons. The early phases of expression are mediated by a redistribution of AMPA-type glutamate receptors: More receptors are added to potentiate the synapse or receptors are removed to weaken synapses. With time, structural changes become apparent, which in general require the synthesis of new proteins. The investigation of the molecular and cellular mechanisms underlying these forms of synaptic plasticity has received much attention, because NMDA receptor–dependent LTP and LTD may constitute cellular substrates of learning and memory.Long-term synaptic plasticity is a generic term that applies to a long-lasting experience-dependent change in the efficacy of synaptic transmission. Here we will focus on N-methyl-d-aspartate (NMDA) receptor–dependent synaptic potentiation (LTP) and depression (LTD), two forms of activity-dependent long-term changes in synaptic efficacy that have been extensively studied. Because both LTP and LTD are believed to represent cellular correlates of learning and memory, they have attracted considerable interest. In this article we will focus on the molecular and cellular mechanisms associated with LTP and LTD. As for other forms of long-term synaptic plasticity, a characterization of LTP and LTD involves describing the molecular mechanisms that are required to elicit the change (induction), followed by an investigation of the mechanism of expression (hours) and maintenance (days). The best-characterized form of NMDA receptor (NMDAR)-dependent LTP occurs between CA3 and CA1 pyramidal neurons of the hippocampus (Fig. 1). Throughout the chapter we will mostly refer to this specific form of LTP. At these CA3-CA1 Schaffer collateral synapses, the loci of both induction and expression are situated in the postsynaptic neuron.Open in a separate windowFigure 1.NMDAR-dependent LTD and LTP in the hippocampus. (A) Historical drawing by Ramon y Cajal (1909) of the trisynaptic pathway in the hippocampus. LTP and LTD are induced by activation of NMDARs at synapses between CA3 and CA1 pyramidal neurons (blue and red). In contrast, LTP at mossy fiber synapses onto CA3 neurons (green on blue) is NMDAR-independent. (B) This electron microscopy image shows the densely packed neuropil in the CA1 region of the hippocampus and highlights two asymmetric CA3-CA1 synapses. Note the typical “bouton en passant” configuration of synapse 1 and the prominent spine in synapse 2. The postsynaptic densities (PSDs) are visible. Scale bar, 200 nm. (Image kindly provided by Rafael Luján, Universitad de Castilla-La Mancha.) (C) Bidirectional change in CA3-CA1 synaptic efficacy by LTD and LTP in the same synapses monitored by extracellular field recordings in an acute slice preparation of the hippocampus. Note the contrasting induction protocols (Data from C Lüscher, unpubl.).     

Modulation of Synaptic Vesicle Exocytosis in Muscle-Dependent Long-Term Depression at the Amphibian Neuromuscular Junction

We have labeled recycling synaptic vesicles at the somatic Bufo marinus neuromuscular junction with the styryl dye FM2-10 and provide direct evidence for refractoriness of exocytosis associated with a muscle activity-dependent form of long-term depression (LTD) at this synapse. FM2-10 dye unloading experiments demonstrated that the rate of vesicle exocytosis from the release ready pool (RRP) of vesicles was more than halved in the LTD (induced by 20 min of low frequency stimulation). Recovery from LTD, observed as a partial recovery of nerve-evoked muscle twitch amplitude, was accompanied by partial recovery of the refractoriness of RRP exocytosis. Unexpectedly, paired pulse plasticity, another routinely used indicator of presynaptic forms of synaptic plasticity, was unchanged in the LTD. We conclude that the LTD induces refractoriness of the neuromuscular vesicle release machinery downstream of presynaptic calcium entry.     

Role of AMPA receptor trafficking in NMDA receptor-dependent synaptic plasticity in the rat lateral amygdala

Stimulated exocytosis and endocytosis of post-synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid subtype of glutamate receptors (AMPARs) have been proposed as primary mechanisms for the expression of hippocampal CA1 long-term potentiation (LTP) and long-term depression (LTD), respectively. LTP and LTD, the two most well characterized forms of synaptic plasticity, are thought to be important for learning and memory in behaving animals. Both LTP and LTD can also be induced in the lateral amygdala (LA), a critical structure involved in fear conditioning. However, the role of AMPAR trafficking in the expression of either LTP or LTD in this structure remains unclear. In this study, we show that NMDA receptor-dependent LTP and LTD can be reliably induced at the synapses of the auditory thalamic inputs to the LA in brain slices. The expression of LTP was prevented by post-synaptic blockade of vesicle-mediated exocytosis with application of a light chain of Clostridium tetanus neurotoxin and was associated with increased cell-surface AMPAR expression. In contrast, the expression of LTD was prevented by post-synaptic application of a glutamate receptor 2-derived interference peptide, which specifically blocks the stimulated clathrin-dependent endocytosis of AMPARs, and was correlated with a reduction in plasma membrane-surface expression of AMPARs. These results strongly suggest that regulated trafficking of post-synaptic AMPARs is also involved in the expression of LTP and LTD in the LA.     

The Cdk5 inhibitor Roscovitine increases LTP induction in corticostriatal synapses

In corticostriatal synapses, LTD (long-term depression) and LTP (long-term potentiation) are modulated by the activation of DA (dopamine) receptors, with LTD being the most common type of long-term plasticity induced using the standard stimulation protocols. In particular, activation of the D1 signaling pathway increases cAMP/PKA (protein kinase A) phosphorylation activity and promotes an increase in the amplitude of glutamatergic corticostriatal synapses. However, if the Cdk5 (cyclin-dependent kinase 5) phosphorylates the DARPP-32 (dopamine and cAMP-regulated phosphoprotein of 32 kDa) at Thr⁷⁵, DARPP-32 becomes a strong inhibitor of PKA activity. Roscovitine is a potent Cdk5 inhibitor; it has been previously shown that acute application of Roscovitine increases striatal transmission via Cdk5/DARPP-32. Since DARPP-32 controls long-term plasticity in the striatum, we wondered whether switching off CdK5 activity with Roscovitine contributes to the induction of LTP in corticostriatal synapses. For this purpose, excitatory population spikes and whole cell EPSC (excitatory postsynaptic currents) were recorded in striatal slices from C57/BL6 mice. Experiments were carried out in the presence of Roscovitine (20 μM) in the recording bath. Roscovitine increased the amplitude of excitatory population spikes and the percentage of population spikes that exhibited LTP after HFS (high-frequency stimulation; 100Hz). Results obtained showed that the mechanisms responsible for LTP induction after Cdk5 inhibition involved the PKA pathway, DA and NMDA (N-methyl-D-aspartate) receptor activation, L-type calcium channels activation and the presynaptic modulation of neurotransmitter release.