Calcineurin-mediated LTD of GABAergic inhibition underlies the increased excitability of CA1 neurons associated with LTP

Coincident pre- and postsynaptic activity generates long-term potentiation (LTP), a possible cellular model of learning and memory. LTP has two components: (1) an increase in the excitatory postsynaptic potential (EPSP), and (2) an increase in the ability of the EPSP to generate a spike (E-S coupling of LTP). We have used pharmacological and genetic approaches to address the molecular nature of E-S coupling in CA1 pyramidal neurons. Blockade of the Ca2+-sensitive phosphatase, calcineurin, prevents induction of E-S coupling without interfering with LTP of the EPSP. Calcineurin produces its effect on E-S coupling by inducing a long-lasting depression (LTD) of the GABA(A)-mediated inhibitory postsynaptic potentials (IPSPs). This LTD of the IPSP was prevented by blockade of NMDA receptors. Thus, the tetanus that elicits NMDA-dependent LTP mediates a coordinately regulated double function. It produces LTP of the EPSP and, concomitantly, LTD of the IPSP that leads to enhancement of E-S coupling.     

Mechanisms underlying induction and maintenance of long-term potentiation in the hippocampus

Long-term potentiation (LTP) in the hippocampus is accompanied by a number of changes on both sides of the synapse. It is now generally considered that the trigger for initiating LTP is the entry of calcium into the postsynaptic area through the NMDA-associated channel while the mechanism(s) underlying the maintenance of LTP are less well understood and probably involve contributions from both sides of the synapse.     

Optical quantal analysis reveals a presynaptic component of LTP at hippocampal Schaffer-associational synapses

The mechanisms by which long-term potentiation (LTP) is expressed are controversial, with evidence for both presynaptic and postsynaptic involvement. We have used confocal microscopy and Ca(2+)-sensitive dyes to study LTP at individual visualized synapses. Synaptically evoked Ca(2+) transients were imaged in distal dendritic spines of pyramidal cells in cultured hippocampal slices, before and after the induction of LTP. At most synapses, from as early as 10 min to at least 60 min after induction, LTP was associated with an increase in the probability of a single stimulus evoking a postsynaptic Ca(2+) response. These observations provide compelling evidence of a presynaptic component to the expression of early LTP at Schaffer-associational synapses. In most cases, the store-dependent evoked Ca(2+) transient in the spine was also increased after induction, a novel postsynaptic aspect of LTP.     

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.     

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 in hippocampal oriens interneurons: postsynaptic induction,presynaptic expression and evaluation of candidate retrograde factors

Several types of hippocampal interneurons exhibit a form of long-term potentiation (LTP) that depends on Ca²⁺-permeable AMPA receptors and group I metabotropic glutamate receptors. Several sources of evidence point to a presynaptic locus of LTP maintenance. The retrograde factor that triggers the expression of LTP remains unidentified. Here, we show that trains of action potentials in putative oriens-lacunosum-moleculare interneurons of the mouse CA1 region can induce long-lasting potentiation of stimulus-evoked excitatory postsynaptic currents that mimics LTP elicited by high-frequency afferent stimulation. We further report that blockers of nitric oxide production or TRPV1 receptors failed to prevent LTP induction. The present results add to the evidence that retrograde signalling underlies N-methyl-d-aspartate (NMDA) receptor-independent LTP in oriens interneurons, mediated by an unidentified factor.     

The biophysical basis underlying the maintenance of early phase long-term potentiation

The maintenance of synaptic changes resulting from long-term potentiation (LTP) is essential for brain function such as memory and learning. Different LTP phases have been associated with diverse molecular processes and pathways, and the molecular underpinnings of LTP on the short, as well as long time scales, are well established. However, the principles on the intermediate time scale of 1-6 hours that mediate the early phase of LTP (E-LTP) remain elusive. We hypothesize that the interplay between specific features of postsynaptic receptor trafficking is responsible for sustaining synaptic changes during this LTP phase. We test this hypothesis by formalizing a biophysical model that integrates several experimentally-motivated mechanisms. The model captures a wide range of experimental findings and predicts that synaptic changes are preserved for hours when the receptor dynamics are shaped by the interplay of structural changes of the spine in conjunction with increased trafficking from recycling endosomes and the cooperative binding of receptors. Furthermore, our model provides several predictions to verify our findings experimentally.     

Posttetanic potentiation and presynaptically induced long-term potentiation at the mossy fiber synapse in rat hippocampus

A form of long-term potentiation (LTP) is induced at the mossy fiber (MF) synapse in the hippocampus by highfrequency presynaptic stimulation (HFS). It is generally accepted that induction of this form of LTP (MF LTP) does not depend on postsynaptic Ca²⁺ current gated by N-methyl-D -aspartate receptors, but it has remained controversial whether induction depends on postsynaptic depolarization and voltage-gated entry of Ca²⁺. There are also contradictory data on the time course of both LTP and post-tetanic potentiation (PTP), a shorter duration form of potentiation observed at MF synapses immediately following HFS. It has been proposed that some of these differences in results may have arisen because of difficulties in isolating monosynaptic responses to MF input. In the present study, whole cell recording was used to observe excitatory postsynaptic currents (EPSCs) elicited in CA3 pyramidal cells by input from MFs. Postsynaptic cells were dialyzed with 1,2-bis(o-aminophenoxy)-ethane-N,N,N′,N′-tetraacetic acid (BAPTA) and F^? to inhibit postsynaptic mechanisms that required Ca²⁺, cells were under voltage clamp during HFS, and conditions were selected to minimize the likelihood of polysynaptic contamination. Under these conditions, HFS nevertheless induced robust LTP (mean magnitude, 62%). The possibility that EPSCs were contaminated by polysynaptic components was investigated by exposing the slices to a suppressing medium (one that partially blocked neurotransmission). EPSC waveforms did not change shape during suppression, indicating that contamination was absent. The LTP observed always was accompanied by prominent PTP that lasted through the first 5 to 15 min following HFS (mean decay time constant, 3.2 min). Induction of this LTP was not cooperative; there was no relationship between the size of responses and the magnitude of the LTP induced. LTP magnitude also was unrelated to the extent to which postsynaptic cells depolarized during HFS. These results show that high rates of presynaptic MF activity elicit robust LTP whether or not there is accompanying postsynaptic depolarization or increase in the concentration of postsynaptic Ca²⁺. High-frequency MF activity also results in a PTP that is unusually large and long. © 1995 John Wiley & Sons, Inc.     

A persistent postsynaptic modification mediates long-term potentiation in the hippocampus

Long-term potentiation (LTP) is a long-lasting enhancement of synaptic transmission that can be induced by brief repetitive stimulation of excitatory pathways in the hippocampus. One of the most controversial points is whether the process underlying the enhanced synaptic transmission occurs pre- or postsynaptically. To examine this question, we have taken advantage of the novel physiological properties of excitatory synaptic transmission in the CA1 region of the hippocampus. Synaptically released glutamate activates both NMDA and non-NMDA receptors on pyramidal cells, resulting in an excitatory postsynaptic potential (EPSP) with two distinct components. A selective increase in the non-NMDA component of the EPSP was observed with LTP. This result suggests that the enhancement of synaptic transmission during LTP is caused by an increased sensitivity of the postsynaptic neuron to synaptically released glutamate.     

Expression mechanisms underlying long-term potentiation: a postsynaptic view

This review summarizes the various experiments that have been carried out to determine if the expression of long-term potentiation (LTP), in particular N-methyl-D-aspartate (NMDA) receptor-dependent LTP, is presynaptic or postsynaptic. Evidence for a presynaptic expression mechanism comes primarily from experiments reporting that glutamate overflow is increased during LTP and from experiments showing that the failure rate decreases during LTP. However, other experimental approaches, such as monitoring synaptic glutamate release by recording astrocytic glutamate transporter currents, have failed to detect any change in glutamate release during LTP. In addition, the discovery of silent synapses, in which LTP rapidly switches on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor function at NMDA-receptor-only synapses, provides a postsynaptic mechanism for the decrease in failures during LTP. It is argued that the preponderance of evidence favours a postsynaptic expression mechanism, whereby NMDA receptor activation results in the rapid recruitment of AMPA receptors as well as a covalent modification of synaptic AMPA receptors.     

Postsynaptic factors control the duration of synaptic enhancement in area CA1 of the hippocampus.

In area of CA1 of the hippocampus, at least two phases of long-term potentiation (LTP) can be isolated: an early decremental component referred to as short-term potentiation (STP), which precedes a long-lasting, nondecremental component commonly considered to be stable LTP. Utilizing the hippocampal slice preparation, experiments were performed to determine the physiological factors controlling the conversion of STP to LTP. The duration of NMDA receptor-dependent synaptic enhancement was influenced by several factors, including the degree of postsynaptic NMDA receptor activation and the magnitude and timing of postsynaptic membrane depolarization during synaptic transmission. It was possible to convert STP to LTP by manipulations that increased the influx of calcium into the postsynaptic cell. These results demonstrate that NMDA receptor activation can result in distinct forms of synaptic potentiation and imply that the magnitude of postsynaptic calcium increase is a critical variable controlling the duration of synaptic enhancement.     

Presynaptic and Postsynaptic Cortical Mechanisms of Chronic Pain

Long-term potentiation (LTP) is a cellular model for learning and memory and believed to be critical for plastic changes in the brain. Depending on the central nervous system region, LTP has been proposed to contribute to many key physiological functions and pathological conditions, such as learning/memory, chronic pain, and drug addiction. While the induction of LTP in general requires activation of postsynaptic glutamate receptors, the expression of LTP can be mediated by postsynaptic mechanisms and/or presynaptic enhancement of glutamate release. In this review, we will evaluate recent progress made in the mechanisms of LTP in the anterior cingulate cortex (ACC) and explore its functional significance in synaptic changes after peripheral injury. Recent findings suggest that while ACC LTP in brain slice preparations is postsynaptically induced and expressed, injury triggered synaptic potentiation in the ACC contains both presynaptic enhancement of glutamate release and postsynaptic potentiation of AMPA receptor-mediated responses. Understanding presynaptic and postsynaptic mechanisms for ACC potentiation may help us to treat chronic pain in near future.     

Selective facilitation of LTP in the ventral hippocampus by calcium stores

The effects of low concentrations of caffeine and ryanodine on field excitatory postsynaptic potentials (EPSPs) and long-term potentiation (LTP) were studied in CA1 region of slices of dorsal and ventral hippocampus (DH and VH, respectively). There was a striking difference between the two regions in the magnitude of effect of both drugs, as well as the ability to interact with a tetanic stimulation to produce LTP. Low concentration of caffeine (1 mM) produced a postsynaptic increase in the slope of population EPSPs in VH, and facilitated LTP in this region. Low concentration of ryanodine (0.2 μM) was able to convert short-term potentiation (STP) to LTP in VH only. These effects are postsynaptic and they reflect a higher concentration of ryanodine receptors (RyRs) in the VH compared to the DH.     

Regulation of AMPA receptor surface diffusion by PSD-95 slots

Excitatory synaptic transmission is largely mediated by AMPA receptors (AMPARs) present at the postsynaptic density. Recent studies in single molecule tracking of AMPAR has revealed that extrasynaptic AMPARs are highly mobile and thus might serve as a readily available pool for their synaptic recruitment during synaptic plasticity events such as long-term potentiation (LTP). Because this hypothesis relies on the cell's ability to increase the number of diffusional traps or 'slots' at synapses during LTP, we will review a number of protein-protein interactions that might impact AMPARs lateral diffusion and thus potentially serve as slots. Recent studies have identified the interaction between the AMPAR-Stargazin complex and PSD-95 as the minimal components of the diffusional trapping slot. We will overview the molecular basis of this critical interaction, its activity-dependent regulation and its potential contribution to LTP.     

Two sides to long-term potentiation: a view towards reconciliation

Almost since the discovery of long-term potentiation (LTP) in the hippocampus, its locus of expression has been debated. Throughout the years, convincing evidence has accumulated to suggest that LTP can be supported either presynaptically, by an increase in transmitter release, or postsynaptically, by an increase in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor number. However, whereas postsynaptic enhancement appears to be consistently obtained across studies following LTP induction, presynaptic enhancement is not as reliably observed. Such discrepancies, along with the failure to convincingly identify a retrograde messenger required for presynaptic change, have led to the general view that LTP is mainly supported postsynaptically, and certainly, research within the field for the past decade has been heavily focused on the postsynaptic locus. Here, we argue that LTP can be expressed at either synaptic locus, but that pre- and postsynaptic forms of LTP are dissociable phenomena mediated by distinct mechanistic processes, which are sensitive to different patterns of neuronal activity. This view of LTP helps to reconcile discrepancies across the literature and may put to rest a decades-long debate.     

铝暴露对大鼠海马神经元长时程增强和Na+通道表达的影响

海马神经元长时程增强(LTP) 被认为与学习和记忆的形成有关.Na⁺在诱导 LTP产生的过程中十分重要.实验发现,慢性铝暴露可以影响大鼠海马神经元LTP的产生,随着铝暴露浓度的增加,LTP 的幅值逐渐降低.RT-PCR 法对大鼠海马神经元 9 种类型Na⁺ 通道（即 Nav1.1～Nav1.9）的 mRNA 进行检测发现,除 Nav1.4 和 Nav1.8 Na⁺通道 mRNA 在大鼠海马神经元中未见表达外,慢性染铝组大鼠海马神经元7种Na⁺ 通道 mRNA 表达均明显增高（P<0.05）.蛋白印迹法对一种脑型 Na⁺通道 (Nav 1.2) 蛋白检测证明, Na⁺通道蛋白表达亦明显升高.结果提示,铝进入神经元后,可能通过影响 Na⁺ 通道蛋白的表达而影响了突触后神经细胞的去极化,进而影响了LTP的诱导过程,从而预示铝的暴露可能损害大鼠学习和记忆能力.     

Adenosine A2A receptors are essential for long-term potentiation of NMDA-EPSCs at hippocampal mossy fiber synapses

The physiological conditions under which adenosine A2A receptors modulate synaptic transmission are presently unclear. We show that A2A receptors are localized postsynaptically at synapses between mossy fibers and CA3 pyramidal cells and are essential for a form of long-term potentiation (LTP) of NMDA-EPSCs induced by short bursts of mossy fiber stimulation. This LTP spares AMPA-EPSCs and is likely induced and expressed postsynaptically. It depends on a postsynaptic Ca2+ rise, on G protein activation, and on Src kinase. In addition to A2A receptors, LTP of NMDA-EPSCs requires the activation of NMDA and mGluR5 receptors as potential sources of Ca2+ increase. LTP of NMDA-EPSCs displays a lower threshold for induction as compared with the conventional presynaptic mossy fiber LTP; however, the two forms of LTP can combine with stronger induction protocols. Thus, postsynaptic A2A receptors may potentially affect information processing in CA3 neuronal networks and memory performance.     

Expression mechanisms underlying long-term potentiation: a postsynaptic view, 10 years on

This review focuses on the research that has occurred over the past decade which has solidified a postsynaptic expression mechanism for long-term potentiation (LTP). However, experiments that have suggested a presynaptic component are also summarized. It is argued that the pairing of glutamate uncaging onto single spines with postsynaptic depolarization provides the final and most elegant demonstration of a postsynaptic expression mechanism for NMDA receptor-dependent LTP. The fact that the magnitude of this LTP is similar to that evoked by pairing synaptic stimulation and depolarization leaves little room for a substantial presynaptic component. Finally, recent data also require a revision in our thinking about the way AMPA receptors (AMPARs) are recruited to the postsynaptic density during LTP. This recruitment is independent of subunit type, but does require an adequate reserve pool of extrasynaptic receptors.     

Presynaptic BDNF required for a presynaptic but not postsynaptic component of LTP at hippocampal CA1-CA3 synapses

Brain-derived neurotrophic factor (BDNF) has been implicated in several forms of long-term potentiation (LTP) at different hippocampal synapses. Using two-photon imaging of FM 1-43, a fluorescent marker of synaptic vesicle cycling, we find that BDNF is selectively required for those forms of LTP at Schaffer collateral synapses that recruit a presynaptic component of expression. BDNF-dependent forms of LTP also require activation of L-type voltage-gated calcium channels. One form of LTP with presynaptic expression, theta burst LTP, is thought to be of particular behavioral importance. Using restricted genetic deletion to selectively disrupt BDNF production in either the entire forebrain (CA3 and CA1) or in only the postsynaptic CA1 neuron, we localize the source of BDNF required for LTP to presynaptic neurons. These results suggest that long-term synaptic plasticity has distinct presynaptic and postsynaptic modules. Release of BDNF from CA3 neurons is required to recruit the presynaptic, but not postsynaptic, module of plasticity.     

On the Mechanism of Synaptic Depression Induced by CaMKIIN,an Endogenous Inhibitor of CaMKII

Activity-dependent synaptic plasticity underlies, at least in part, learning and memory processes. NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) is a major synaptic plasticity model. During LTP induction, Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) is activated, autophosphorylated and persistently translocated to the postsynaptic density, where it binds to the NMDAR. If any of these steps is inhibited, LTP is disrupted. The endogenous CaMKII inhibitor proteins CaMKIINα,β are rapidly upregulated in specific brain regions after learning. We recently showed that transient application of peptides derived from CaMKIINα (CN peptides) persistently depresses synaptic strength and reverses LTP saturation, as it allows further LTP induction in previously saturated pathways. The treatment disrupts basal CaMKII-NMDAR interaction and decreases bound CaMKII fraction in spines. To unravel CaMKIIN function and to further understand CaMKII role in synaptic strength maintenance, here we more deeply investigated the mechanism of synaptic depression induced by CN peptides (CN-depression) in rat hippocampal slices. We showed that CN-depression does not require glutamatergic synaptic activity or Ca²⁺ signaling, thus discarding unspecific triggering of activity-dependent long-term depression (LTD) in slices. Moreover, occlusion experiments revealed that CN-depression and NMDAR-LTD have different expression mechanisms. We showed that CN-depression does not involve complex metabolic pathways including protein synthesis or proteasome-mediated degradation. Remarkably, CN-depression cannot be resolved in neonate rats, for which CaMKII is mostly cytosolic and virtually absent at the postsynaptic densities. Overall, our results support a direct effect of CN peptides on synaptic CaMKII-NMDAR binding and suggest that CaMKIINα,β could be critical plasticity-related proteins that may operate as cell-wide homeostatic regulators preventing saturation of LTP mechanisms or may selectively erase LTP-induced traces in specific groups of synapses.