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.     

突触长时程增强形成机制的研究进展

高等动物脑内突触传递的可塑性是近30年来神经科学研究的热点,突触传递长时程增强（long-term potentiation,LTP)是神经元可塑性的反映,其形成主要与突触后机制有关。过去关于LTP机制的研究主要集中于N－甲基－D门冬氨酸（NMDA）受体的特征及该受体被激活后的细胞内级联反应,现认为脑内存在只具有NMDA受体而不具有α－氨基羟甲基恶唑丙酸（AMPA）受体的“静寂突触（silent synapse)”,这一概念的提出,使人们认识到AMPA受体在LTP表达的突触后机制中的重要作用。     

Presynaptic change associated with long-term potentiation in hippocampus

Long-term potentiation of the hippocampal response to repeated stimulation of rat entorhinal cortex occured concomitantly with a decrease in the excitability of presynaptic terminals. It is, therefore, possible that the long-term potentiation is caused, at least partly, by an enhancement of presynaptic efficacy.     

Imaging spatio-temporal patterns of long-term potentiation in mouse hippocampus

Spatio-temporal patterns of neuronal activity before and after the induction of long-term potentiation in mouse hippocampal slices were studied using a real-time high-resolution optical recording system. After staining the slices with voltage-sensitive dye, transmitted light images and extracellular field potentials were recorded in response to stimuli applied to CA1 stratum radiatum. Optical and electrical signals in response to single test pulses were enhanced for at least 30 minutes after brief high-frequency stimulation at the same site. In two-pathway experiments, potentiation was restricted to the tetanized pathway. The optical signals demonstrated that both the amplitude and area of the synaptic response were increased, in patterns not predictable from the initial, pretetanus, pattern of activation. Optical signals will be useful for investigating spatio-temporal patterns of synaptic enhancement underlying information storage in the brain.     

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.     

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.     

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.     

Short- and long-term potentiation in afferent pathways of the neonatal rabbit hippocampus

Vocal potentials were recorded in hippocampal area CA₁ and dentate fascia in unanesthetized rabbits aged from 1 to 50 days during stimulation of Schaffer's collaterals and the perforant path, respectively, with paired (interval 15–100 msec) and repetitive (20–40 Hz for 3–5 sec) electric pulses. Short-term potentiation of focal potentials during paired stimulation and post-tetanic potentiation lasting from a few minutes to 3 h were shown to be reproduced in the hippocampus from the first days after birth, whereas in the dentate fascia, which matures later, reproduction began on the 8th–10th day, when neurons first began to respond to stimulation of the corresponding afferent pathways.     

β-淀粉样蛋白抑制海马长时程增强机制的研究进展

认知、学习和记忆功能的进行性下降,是阿尔采末病（AD）的主要临床特征,其发病机制一般认为与β-淀粉样蛋白（Aβ）在脑内的沉积以及由此产生的神经毒性作用有关。海马长时程增强（LTP）是反映突触传递可塑性的重要指标之一,被认为与学习和记忆的形成有关。本文结合近年来对离体、在体以及转基因动物多方面的研究进展,扼要介绍了Aβ及其活性片段对海马LTP的影响,并从离子通道／受体、蛋白激酶、逆行信使和基因突变等方面阐述了Aβ抑制LTPT的可能机制。     

Suppression of associative long-term potentiation in the hippocampus after tetanization of reinforcing afferents

Field potentials (FP) induced in area C1 by gentle orthodromic stimulation were recorded in murine hippocampal slices and associative long-term potentiation (ALTP) produced by C2 tetanization associated with intensive tetanization of another group of fibers (C1) was investigated. A comparison was made between the effects of additional C1 tetanization produced at 50–300 msec before and after combined tetanization of both afferents. Where these intervals measured 50–200 msec, preliminary tetanization of C1 suppressed ALTP (rise in FP amplitude: 10.4±5.2%) in comparison with the regimen whereby additional C1 tetanization came later (giving a rise of 32.4±5.3%); no significant difference was noted at an interval of 300 msec. The three possible reasons for ALTP suppression are discussed, namely: inactivation of "fast" calcium channels, post-activation hyperpolarization of postsynaptic neurons, and synaptic inhibition. The ALTP suppression mechanism is thought to resemble that underlying the relative inefficacy of "reversible" combinations in the shaping of behavioral conditioned reflexes.Institute for Brain Research, Academy of Medical Sciences of the USSR, Moscow. Institute of Chemical Physics, Academy of Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 21, No. 5, pp. 636–643, September–October, 1989.     

A focal adhesion-like process underlies induction of long-term potentiation in the Schaffer collateral-CA1 region of the hippocampus

In the series of experiments reported here we provide evidence that a focal adhesion-like process underlies the induction of long-term potentiation (LTP) in the Schaffer Collateral-CA1 projection in the hippocampus. Here we show that an integrin binding peptide (RGD) impairs induction of Schaffer Collateral-CA1 LTP in hippocampal slice preparations in vitro. The heparin-binding peptide that binds heparan sulfate proteoglycan (HSPG) and blocks the formation of focal adhesions also impairs induction of LTP. Either the integrin-binding peptide or heparin-binding peptide reduces LTP partially. However, when the two peptides were administered simultaneously, there was no LTP 1 hour after induction. This indicates that these two molecules might function together and that a focal adhesion-like process might be involved in the induction of LTP. Additionally,we report that the RGD effect on LTP is time dependent and occurs only in the first few minutes following LTP induction, that the binding of the RGD peptide in CA1 stratum radiatum increases after LTP induction and that this increased binding depends on Ca(2+). Using electron microscopy we show that integrins are present in synapses.     

小鼠在体海马长时程增强记录技术

目的:建立记录小鼠在体海马"前穿通纤维-齿状回"(PP-DG)神经通路长时程增强(LTP)的方法.方法:动物麻醉后固定于立体定位仪上,参照立体定位参数将刺激电极插入至前穿通纤维,记录电极插入至DG颗粒细胞层,而后进行LTP的诱发和记录.结果:对各种实验条件优化后,成功记录了Balb/c小鼠海马PP-DG通路LTP.应用该方法对快速老化模型小鼠(SAM)的快速老化亚系SAMP8和抗快速老化亚系SAMRl海马神经突触可塑性进行考察,结果表明在体海马LTP与脑片LTP和行为学实验结果相符.结论:成功建立了小鼠在体海马PP-DG通路LTP的记录方法,可用于整体动物神经突触可塑性的评价.     

Effects of hyperdynamic fields on input-output relationships and long-term potentiation in the rat hippocampus

The effects of a 2G force environment on synaptic plasticity were examined in the rat hippocampus. Field potentials from neurons in the CA1 pyramidal cell layer were evoked by stimulation of the afferent Schaffer collateral/commissural fibers in an in vitro slice preparation. Input-output (I-O) relationships of the circuit were determined before and after tetanizing stimuli given to induce long term potentiation (LTP), a form of neural plasticity. I-O curves from animals exposed to 2G via centrifugation for either 2 or 14 days were not different from those obtained in control (1G) animals. Similarly, induction of LTP was equivalent in all groups, showing increases in maximum amplitude, slope and midpoint response of the fitted Boltzmann functions compared to un-tetanized controls. Comparison of slices from dorsal and ventral hippocampus showed the location of the slice had no effect of LTP expression. We conclude that, in contrast to other reports of functional changes in the central nervous system under altered force environments, cellular mechanisms of synaptic plasticity, which may underlie learning and memory, are preserved in the hippocampus.     

Opioid receptor dependent long-term potentiation: Peptidergic regulation of synaptic plasticity in the hippocampus

Rapid progress has been made towards understanding the synaptic physiology of excitatory amino acid transmission in the hippocampus. By comparison, the function of opioid peptides localized to some of the same pathways which use glutamate for fast excitation is poorly understood. Here I consider new evidence specifically implicating opioid peptides in long-term potentiation (LTP) induced by high-frequency stimulation of pathways which combine glutamate and opioid neurotransmission. This form of LTP is unique in that it depends on activation of opioid receptors, and unlike many excitatory systems in brain, it does not require activation of the (NMDA) type of glutamate receptor. Thus one of the main functions of opioids in the hippocampus may be to regulate activity-dependent changes in synaptic strength and neuronal excitability. At another level, “opioid” LTP may provide basic insights into peptidergic transmission and its functional interactions with classical neurotransmitters in the brain.     

A synaptic model for pain: long-term potentiation in the anterior cingulate cortex

Investigation of molecular and cellular mechanisms of synaptic plasticity is the major focus of many neuroscientists. There are two major reasons for searching new genes and molecules contributing to central plasticity: first, it provides basic neural mechanism for learning and memory, a key function of the brain; second, it provides new targets for treating brain-related disease. Long-term potentiation (LTP), mostly intensely studies in the hippocampus and amygdala, is proposed to be a cellular model for learning and memory. Although it remains difficult to understand the roles of LTP in hippocampus-related memory, a role of LTP in fear, a simplified form of memory, has been established. Here, I will review recent cellular studies of LTP in the anterior cingulate cortex (ACC) and then compare studies in vivo and in vitro LTP by genetic/ pharmacological approaches. I propose that ACC LTP may serve as a cellular model for studying central sensitization that related to chronic pain, as well as pain-related cognitive emotional disorders. Understanding signaling pathways related to ACC LTP may help us to identify novel drug target for various mental disorders.     

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.     

A model of late long-term potentiation simulates aspects of memory maintenance

Late long-term potentiation (L-LTP) denotes long-lasting strengthening of synapses between neurons. L-LTP appears essential for the formation of long-term memory, with memories at least partly encoded by patterns of strengthened synapses. How memories are preserved for months or years, despite molecular turnover, is not well understood. Ongoing recurrent neuronal activity, during memory recall or during sleep, has been hypothesized to preferentially potentiate strong synapses, preserving memories. This hypothesis has not been evaluated in the context of a mathematical model representing ongoing activity and biochemical pathways important for L-LTP. In this study, ongoing activity was incorporated into two such models - a reduced model that represents some of the essential biochemical processes, and a more detailed published model. The reduced model represents synaptic tagging and gene induction simply and intuitively, and the detailed model adds activation of essential kinases by Ca(2+). Ongoing activity was modeled as continual brief elevations of Ca(2+). In each model, two stable states of synaptic strength/weight resulted. Positive feedback between synaptic weight and the amplitude of ongoing Ca(2+) transients underlies this bistability. A tetanic or theta-burst stimulus switches a model synapse from a low basal weight to a high weight that is stabilized by ongoing activity. Bistability was robust to parameter variations in both models. Simulations illustrated that prolonged periods of decreased activity reset synaptic strengths to low values, suggesting a plausible forgetting mechanism. However, episodic activity with shorter inactive intervals maintained strong synapses. Both models support experimental predictions. Tests of these predictions are expected to further understanding of how neuronal activity is coupled to maintenance of synaptic strength. Further investigations that examine the dynamics of activity and synaptic maintenance can be expected to help in understanding how memories are preserved for up to a lifetime in animals including humans.     

Permissive role of insulin in the expression of long-term potentiation in the hippocampus of immature rats

Many studies indicate that impairment in insulin signaling leads to learning and memory deficits. However, previous studies failed to establish a clear role of insulin in long-term potentiation (LTP), the best cellular model of memory formation. Here we show that while insulin pretreatment did not affect LTP magnitude in the adult rat hippocampus, it facilitated LTP expression in the immature hippocampus. The tyrosine kinase inhibitor AG-1024 abolished the effect of insulin in young rats, suggesting the involvement of the insulin receptor. On the other hand, increasing extracellular glucose concentration failed to facilitate LTP and application of an insulin-responsive glucose transporter-4 inhibitor did not impair the effect of insulin. These results suggest that the facilitatory action of insulin on LTP is not an indirect effect on glucose homeostasis/utilization. Involvement of the MAPK/ERK pathway, a known downstream pathway of insulin signaling, was revealed by pretreatment with PD98059, which blocked the insulin-mediated LTP facilitation. Consistent with this, high-frequency stimulation induced a significant increase in the level of phosphorylated Erk-2 in insulin-treated hippocampus. Taken together, these results suggest that insulin may be an essential factor in the immature brain, allowing the expression of LTP to facilitate learning and memory.     

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.