Involvement of NMDA receptors and voltage-dependent calcium channels on augmentation of long-term potentiation in hippocampal CA1 area of morphine dependent rats

The involvement of NMDA receptors and voltage-dependent calcium channels on augmentation of long-term potentiation (LTP) was investigated at the Schaffer collateral–CA1 pyramidal cell synapses in hippocampal slices of morphine dependent rats, using primed-bursts tetanic stimulation. The amplitude of population spike was measured as an index of increase in postsynaptic excitability. d,l-AP5 and nifedipine were used as NMDA receptor antagonist and voltage-dependent calcium channel blocker, respectively. The amount of LTP of orthodromic population spike amplitude was higher in slices from dependent rats. Perfusion of slices from control or dependent rats with ACSF containing either d,l-AP5 (25 μM) or nifedipine (10 μM) and delivering tetanic stimulation, showed that d,l-AP5 completely blocked LTP of OPS in slices from both control and dependent rats, while nifedipine attenuated the amount of LTP of OPS in dependent slices and had no effect on control ones. The results suggest that the enhanced LTP of OPS in the CA1 area of hippocampal slices from morphine dependent rats is primarily induced by the NMDA receptors activity and the voltage-dependent calcium channels may also be partially involved in the phenomenon.     

应激和吗啡对不同周龄大鼠海马CA1区突触可塑性的影响

目的研究慢性应激和(或)吗啡对不同周龄Wistar大鼠海马CA1区突触可塑性的影响。方法将4周龄和10周龄(各51只)雄性Wistar大鼠分别随机分为对照组(分别为14只)、慢性应激组(分别为13只和11只)、吗啡组(分别为14只和13只)和慢性应激加吗啡组(分别为10只和13只)。以场兴奋性后电位(fEPSP)的幅值观察两个年龄段各组大鼠的突触可塑性变化。结果(1)长时程增强(LTP)：对照组、慢性应激组和吗啡组均为10周龄鼠大于4周龄鼠(P＜0.01)；慢性应激削弱了4周龄和10周龄大鼠LTP[分别为(106.8±0.3)%,(115.6±0.2)％]；吗啡易化了10周龄大鼠的LTP(135.7±0.4)%,却削弱了4周龄大鼠的LTP(105.0±0.2)%；慢性应激加吗啡组削弱了10周龄大鼠的LTP(116.7±0.3)%,却易化了4周龄的LTP(117.7±0.5)%,均P＜0.05。(2)长时程抑制(LTD)：慢性应激后10周龄大鼠不能诱导出LTD(103.9±0.3)%,却易化4周龄大鼠的LTD(88.6±0.3)%；吗啡对10周龄和4周龄大鼠的LTD均起易化作用[分别为(77.5±0.2)%,(86.4±0.5)%]；10周龄慢性应激的大鼠使用吗啡后不能诱导出LTD(110.4±0.3)%,但对4周龄大鼠的LTD起易化作用(79.1±0.2)%,均P＜0.05。结论慢性应激和(或)急性吗啡暴露分别对4周龄与10周龄大鼠海马CA1区的LTP和LTD有不同作用,存在明显的年龄差异。     

不同刺激对条件性恐惧大鼠行为及海马CA1区突触可塑性的影响

目的研究不同刺激对条件性恐惧大鼠的行为、海马CA1区兴奋性突触后电位（EPSP）的长时程增强（LTP）及长时程抑制（LTD）的影响。方法将106只大鼠分为7个实验组和4个行为对照组，检测其活体海马CA1区EPSP的LTP和LTD。（1）应激：①空白对照组（11只）除外，将6个实验组大鼠分别在A箱（应激箱）和B箱（非应激箱）中适应2d，第3天在A箱中给予20个条件性光刺激（CS）和足底电击（应激），将②急性应激组（8只）在应激后立即检测，③无暴露组（11只）在应激后24h后检测；（2）行为学观察：第4天将其余4组分别暴露于A箱（④A暴露组，17只）和B箱（⑤B暴露组，11只）中，并在不同刺激下（⑥A暴露＋1CS组，10只；⑦B暴露＋1CS组，11只）观察其僵住行为（共1h，分3个连续时相，每个时相20min；自第3个时相开始时给予或不给予1次CS）。随后进行检测。相应的4个行为对照组大鼠接受与④一⑦组同样的处理，但不予电击和EPSP检测。结果（1）僵住行为：各实验组在3个时相中的僵住时间比例均高于各自的对照组（P≤O．01）。在第3个时相中，A暴露组、A暴露＋1CS组、B暴露＋1CS组的僵住时间比例均高于B暴露组（P≤0．01）。（2）EPSP：经高频刺激，除急性应激组和A暴露＋1CS组外，空白对照组、无暴露组、A暴露组、B暴露组和B暴露＋1CS组均诱导出m（P〈0．01和P〈0．05）。经低频刺激后，急性应激组和A暴露＋1CS组大鼠的海马CA1区可稳定地诱导出LTD（P〈O．01和P〈0．05）。结论不同刺激可引起条件性恐惧大鼠长时间的僵住行为，其海马CA1区突触可塑性发生异质性改变。     

Proline-induced inhibition of glutamate release in hippocampal area CA1

The amino acid proline has long been suspected to serve as a modulator of synaptic transmission in the mammalian brain, but no such function has been identified. The selective expression of high affinity proline transport by a subset of glutamate pathways suggested that proline might play a role in synaptic transmission at these sites. This idea was tested with use of one such pathway, the Schaffer collateral-commissural projection to CA1 pyramidal cells of the rat hippocampus. Proline enhanced the initial slope of the field EPSP without affecting axonal excitability or the magnitude of paired-pulse facilitation. Proline-induced potentiation far outlasted the period of proline application and required the activation of NMDA receptors. Proline enhanced Schaffer collateral-commissural synaptic transmission even when the connections between areas CA1 and CA3 had been interrupted. Potentiation was observed with a proline concentration normally present in human CSF (3 μM). A concentration typical of CSF in persons with the genetic disorder hyperprolinemia type II (30 μM) produced a somewhat greater effect. Occlusion experiments suggested that proline-induced potentiation and tetanus-induced long-term potentiation utilize largely distinct transduction mechanisms. Proline-induced potentiation could be blocked by a prior high frequency stimulus, whether or not the stimulus evoked long-term potentiation. These results suggest that endogenous extracellular proline regulates the basal function of some glutamate synapses by maintaining them in a partially potentiated state. They may also facilitate understanding of the seizures and/or mental retardation associated with genetic disorders of proline metabolism.     

Chronic in vivo morphine administration facilitates primed-bursts-induced long-term potentiation of Schaffer collateral–CA1 synapses in hippocampal slices in vitro

In this study, the effects of chronic morphine administration (20–30 days) on long-term potentiation (LTP) were investigated at the Schaffer collateral–CA1 pyramidal cell synapses of the rat hippocampal slices. Orthodromic population spike (OPS) amplitude and delay (peak latency) were measured as indices of increase in synaptic efficacy. The amounts of LTP of OPS delay and LTP of OPS amplitude were higher in slices from dependent rats. Perfusion of slices from control and dependent rats with morphine containing ACSF and delivering tetanic stimulation, showed that short-term presence of morphine could not mimic the LTP enhancing effects of chronic morphine administration, however, attenuated the amount of LTP of OPS amplitude in slices of dependent rats. This study supports the hypothesis that the susceptibility of CA1 synapses to plastic changes increases by chronic, not acute exposure to morphine and suggests that a withdrawal phenomenon might be an underlying mechanism for the observed augmented LTP of OPS amplitude in slices of dependent rats.     

Developmental changes in long-term potentiation in CA1 of rat hippocampal slices

Long-term potentiation (LTP) was examined in the CA1 region of rat hippocampal slices at postnatal day 9 (P9), P15, P30, P60, P90, P120, and P300. A single 100 Hz × 1 sec tetanus failed to induce LTP in P9 slices, while similar degrees of LTP were observed at P15, P30, and P60. At P30, changes in population spike (PS) amplitudes were accurately predicted by changes in dendritic excitatory postsynaptic potentials (EPSPs). However, at P15, the predicted increase in PS calculated from corresponding changes in dendritic EPSPs was significantly less than the observed increase, suggesting that EPSP-PS dissociation (ES-dissociation) plays a substantial role in LTP at P15. Additionally, the corresponding changes in somatic EPSP height measured in the CA1 cell layer did not predict the E-S dissociation at P15, suggesting that the E-S dissociation arises largely from changes in the excitability of the soma. Using a single 100 Hz × 1 sec tetanus, LTP proved difficult to induce in slices from rats ≥ P90, with slices showing initial enhancement that faded over 60 min of monitoring. © 1995 Wiley-Liss, Inc.     

Estrogen modulates sexually dimorphic contextual fear conditioning and hippocampal long-term potentiation (LTP) in rats

The present study examined the role of ovarian steroids in contextual fear conditioning and hippocampal synaptic plasticity in female rats. In experiment 1, adult female rats were ovariectomized and submitted to contextual fear conditioning, a procedure in which rats received unsignaled footshock in a novel observation chamber; freezing behavior served as the measure of conditional fear. Ovariectomized female rats froze at levels comparable to male rats, both of which froze significantly more than sham-operated female rats. In experiment 2, estrogen replacement in ovariectomized female rats reduced fear conditioning to a level comparable to that of sham-operated females in experiment 1. In experiment 3, the influence of estrogen on the induction of long-term potentiation (LTP) at perforant path-dentate granule cell synapses in ovariectomized female rats was examined. Estrogen decreased both population spike LTP and EPSP-spike potentiation at perforant path synapses. Taken together, these experiments indicate that ovarian steroids regulate both sexually dimorphic behavior and hippocampal plasticity in a fear-conditioning paradigm.     

Prolonged enhancement of synaptic transmission in area CA1 of rat hippocampal slices induced by NaF/AlCl3 does not require NMDA receptor activation but is suppressed by inhibitors of phosphoinositide-mediated signalling pathways

The processes underlying the action of AlF₄⁻ (10 mM NaF/10 μM AlCl₃) in inducing long-lasting enhancement of synaptic transmission in area CA1 of rat hippocampal slices have been investigated. Exposure of hippocampal slices to AlF₄⁻ for 10 min caused population EPSP slope to rise by approximately 50% within 60 min of washing off the NaF/AlCl₃ saline. This effect was not inhibited either by APV (50 μM), or by temporary interruption of the delivery of test stimuli during and for up to 20 min after application of the AlF₄⁻-containing medium. However, pretreatment of preparations with either thapsigargin (1 μM) or staurosporine (1 μM), or ommission of Ca²⁺ from the AlF₄⁻-containing saline (no addition of EGTA) prevented the potentiating action of NaF/AlCl₃. We conclude that the potentiating effect of AlF₄⁻ is via a G-protein linked to phosphoinositide turnover, and that both arms of this signalling pathway are necessary for potentiation to occur. Ca²⁺ influx is also a requirement, but does not occur through the NMDA receptor.     

GABA能去抑制水平的变化对海马CAl突触长时程增强的影响

目的 研究改变中间神经元GABA能抑制水平对海马CA1区突触长时程增强(LTP)的影响.同时获得不同浓度Bicuculline阻断GABAA受体介导抑制以及影响海马CA1区突触可塑性详细信息. 方法 应用膜片钳全细胞记录技术记录成年小鼠海马脑片上自发的微小的抑制性突触后电位(mIPSC)和诱发的前馈抑制性突触后电流(IPSC),使用细胞外电生理方法 记录刺激Schaffer侧枝诱发的CA1区辐射层场的兴奋性突触后电位(fEPSP],测量不同浓度Bicuculline对mIPSC、IPSC和fEPSP的作用,以及它们对小鼠海马脑片CA1区突触LTP的影响. 结果 10μmol/L、20μmol/L Bicuculline可以减弱mIPSC和IPSC抑制性突触电流,且20 μmol/L Bicuculline作用更明显;20μmol/L Bicuculline可以明显提高fEPSP的斜率,而5 μmol/L和10 μmol/LBicuculline没有明显作用;5 μmol/L、10 μmol/L、20μmol/L和50μmol/L Bicuculline组100赫兹强直刺激诱发后的fEPSP平均斜率均值都大于对照组,但仅10 μmol/L、20 μmol/L两组相比,差异有统计学意义(P<0.05). 结论 Bicuculline可以减弱GABAA受体介导的抑制以及增加场的fEPSP斜率,并且Bicuculline阻断GABA能抑制到一个关键水平才可以增强海马CA1区突触的LTP.     

Induction and transient suppression of long-term potentiation in the peri- and postrhinal cortices following theta-related stimulation of hippocampal field CA1

During behavioral events associated with periods of likely mnemonic processing, CA1 pyramidal cells in rats typically discharge repetitively in either high-frequency bursts (`complex spikes') or single spikes, both of which are tightly phase-locked to the hippocampal theta rhythm. Interestingly, patterned stimulation which mimics the repetitive, learning-related complex spike discharges are optimal for inducing long-term potentiation (LTP) of excitatory field potentials in CA1, and patterned stimulation which mimics the theta-related single action potentials results in a robust and lasting depotentiation at these same synapses. The aim of the present study was to determine the extent to which these physiologically-relevant patterns of hippocampal stimulation have similar effects on synaptic efficacy in the monosynaptic projection from CA1 to the perirhinal and postrhinal cortices (PRh), areas thought to play a prominent role in many forms of learning and memory. Single-pulse stimulation of CA1 evoked a small amplitude, short latency population excitatory postsynaptic potential (EPSP) in the PRh. Theta-burst stimulation (TBS; n=8) delivered to CA1 reliably potentiated the PRh EPSP slope for at least 30 min. Theta-pulse stimulation (TPS; 5 Hz; n=4) delivered to CA1 5 min after TBS substantially but transiently suppressed EPSP slope relative to that of potentiated control preparations. Collectively these data suggest that theta-related patterns of hippocampal activation can reliably induce and transiently suppress LTP in PRh, and are consistent with the notion that behaviorally-relevant, theta-modulated patterns of CA1 unit activity may result in both long- and short-term alterations of synaptic strength within their rhinal cortical targets.     

Perfusion with high potassium plus glutamate can cause LTP erasure or persistent loss of neuronal responsiveness in the CA1 region of the hippocampal slice

Brief perfusion of salines containing elevated (10.5−50mM) [K⁺] plus glutamate (2.5 or 5 mM) could erase long-term protentiation (LTP) in rat hippocampal slices. Prolonged perfusion with high-[K⁺]/glutamate could cause persistent neuronal depression lasting > 1 h. LTP erasure occurred in the absence of generalized depression of axonal responsiveness, while persistent neuronal depression was associated with a failure of antidromic invasion of cells. The protocols used may contribute to the development of a model for the cellular study of memory loss following neurological dysfunction.     

Heat-shock pretreatment prevents suppression of long-term potentiation induced by scopolamine in rat hippocampal CA1 synapses

We examined the effect of heat-shock pretreatment on long-term potentiation (LTP) in the CA1 hippocampal slices of the rat using the muscarinic blocker scopolamine as the LTP (memory) suppressor. Time course study using immunohistochemical techniques indicated peak expression of HSP70 16 h after heat-shock treatment. Focusing on that time point we found tetanic stimulation (at 100 Hz) induced LTP of 191.1+/-12.2% in control slices (n=7), which was suppressed by scopolamine to 114.5+/-2.8 %. Heat-shock pretreatment successfully prevented such suppression (216.6+/-38.2% and 190.2+/-10.6% with and without scopolamine, respectively, n=7). Both HSP expression and LTP responses were relatively small taken either 2 or 48 h after heat-shock or sham pretreatment. These results suggest that the induction of HSPs is time-dependent and can prevent scopolamine-mediated LTP suppression.     

Post-weaning social isolation of rats leads to a diminution of LTP in the CA1 to subiculum pathway

Post-weaning social isolation of rats produces psychological and physiological changes that are relevant to schizophrenia. Here, we report that long-term potentiation (LTP) in the CA1 to subiculum pathway is lower by 34%, (P<0.0001) in brain slices from isolates compared with those from socially housed rats. We also report that LTP in this pathway is NMDA receptor-dependent.     

NCAM-antibodies modulate induction of long-term potentiation in rat hippocampal CA1

The neural cell adhesion molecule (NCAM) probably plays a role in neural plasticity in the adult vertebrate brain. We here present evidence that NCAM may be involved in long-term potentiation (LTP) in the CA1-region of rat hippocampal slices. It is shown that local application of antibodies against NCAM inhibits subsequent LTP-induction. Thus NCAM may be directly involved in the initial phase of LTP-induction. These results have important implications for the possible involvement of NCAM in learning and memory.     

Epileptic-like activity induces multiple forms of plasticity in hippocampal area CA1

Mesial temporal lobe epilepsy is a relatively common form of epilepsy that afflicts many thousands of people. It has been suggested that the development of primary and secondary foci may involve mechanisms similar to long-term potentiation (LTP). In vitro seizure models typically involve an increase in spontaneous asynchronous bursting activity (epileptiform activity) induced either by increasing excitation or decreasing inhibition. Previous experiments have indicated that these models often generate bursting activity that closely resembles epileptic activity. LTP is often observed following epileptiform activity. In area CA1 of the hippocampus two forms of LTP that are dependent on the activation of either the L-type voltage dependent calcium channel (vdccLTP) or the N-methyl-D-aspartate receptor/channel (nmdaLTP) have been described. It is unclear from previous experiments which type of LTP results from epileptiform activity. Recent evidence indicates that nmdaLTP is most likely a short-term type of plasticity while vdccLTP may be a long-lasting form of synaptic plasticity. Given the characteristics of vdccLTP it is a likely candidate mechanism to underlie the development and formation of secondary seizure foci. We have therefore tested the ability of epileptiform activity induced by elevated potassium chloride to induce multiple forms of LTP in area CA1 of the rat hippocampus. Elevation of extracellular potassium chloride resulted in spontaneous asynchronous bursting. The net result of the spontaneous asynchronous bursting was to induce a compoundLTP consisting of nmdaLTP and vdccLTP components.     

Afferent high strength tetanizations favour potentiation of the NMDA vs. AMPA receptor-mediated component of field EPSP in CA1 hippocampal slices of rats

Long-term potentiation (LTP) of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor-mediated components of 'dual-component' field excitatory postsynaptic potentials (fEPSP-A and fEPSP-N) was studied in the CA1 stratum radiatum in hippocampal slices of rats. Relative degrees of LTP of these fEPSP components were compared for tetanizations with low and high strengths. Magnitudes of fEPSP-A and fEPSP-N were estimated in parallel with a least-square fitting of a short-latent (0.1-8.8 ms) fragment of evoked responses by a weighted sum of 'basic' fEPSP-A and fEPSP-N, obtained during a short preliminary application of d-2-amino-5-phosphonovalerate (APV). We found that low-strength tetanizations selectively potentiated fEPSP-A, while high strength tetanizations potentiated both fEPSP components. These results demonstrate in the experiments with parallel measurements of fEPSP-A and fEPSP-N that LTP of these components differ depending on the strength of afferent tetanization. Unequal potentiation of the commissural-collateral and excitatory local-circuit synapses, which presumably contain different amounts of the AMPA and NMDA receptors, is discussed as the most probable explanation for these results.     

Associative long-term potentiation (LTP) among extrinsic afferents of the hippocampal CA3 region in vivo

Monosynaptic perforant path projections to the CA3 region of the hippocampus are anatomically and physiologically substantial pathways that relay cortical input directly to the hippocampus proper. Despite the suggested relevance of these direct pathways in models of information processing within the CA3 region, surprisingly few studies have characterized synaptic plasticity in these direct cortical projections to the CA3 region. We assessed the ability of perforant path projections, and commissural/associational projections to the hippocampal CA3 region to both induce or display associative LTP in vivo. In pentobarbital-anesthetized adult rats, trains delivered to either the medial or lateral perforant pathway at current intensities normally insufficient to induce LTP displayed associative LTP when these same trains were delivered in conjunction with high-intensity trains to the alternate perforant pathway. Similarly, associative LTP is induced at intrinsic commissural/associational–CA3 (C/A–CA3) synapses when weak C/A trains were delivered in conjunction with high-intensity trains to either the medial or lateral perforant pathway. Associative LTP also was observed at medial and lateral perforant path–CA3 synapses when weak perforant path trains were tetanized in conjunction with high-intensity trains delivered to C/A–CA3 synapses. Thus direct perforant path–CA3 synapses and commissural/associational–CA3 synapses can modify and be modified by other CA3 afferents in an associative manner, verifying a requirement for synaptic plasticity explicit in models of autoassociative information processing in the CA3 region.     

NMDA receptor regulation by amyloid-beta does not account for its inhibition of LTP in rat hippocampus

Accumulation of amyloid-beta peptide (Abeta) is widely believed to play a critical role in the pathogenesis of Alzheimer's disease. Although amyloid-containing plaques are a key neuropathological feature of AD, soluble forms of Abeta can interfere with synaptic plasticity in the brain, suggesting that this form of the peptide may be responsible for much of the memory deficit seen early in the disease. Here, we investigate the mechanism underlying the effects of Abeta on long-term potentiation (LTP) in area CA1 of rat hippocampus. Extracellular field recordings were made in area CA1 of hippocampal slices taken from young, adult male rats. A non-toxic concentration of Abeta (200 nM) produced a rapid inhibition of LTP induced by 100 Hz stimulation while having no long-term effect on normal synaptic transmission. The same dose of Abeta had no effect on long-term depression (LTD) induced by 1200 pulses at 1 or 3 Hz. Picrotoxin had no effect on the inhibition of LTP, suggesting Abeta does not act by enhancing GABAergic transmission. Since the LTP induction in this study was dependent on N-methyl-D-aspartate (NMDA) receptor activation, we looked at the effect of Abeta on isolated NMDA receptor-mediated field potentials. Abeta produced a small but significant inhibition of NMDA receptor-mediated synaptic potentials ( approximately 25%). However, a low dose of MK-801 (0.5 microM) that produced a similar inhibition of NMDA potentials had no effect on LTP induction but completely blocked LTD induction. These results suggest that Abeta does not inhibit LTP via effects on NMDA receptors, but rather interferes with a downstream pathway.     

Heterosynaptic long-term depression is facilitated by blockade of inhibition in area CA1 of the hippocampus

Non-associative long-term depression (LTD) of the stratum radiatum input to area CA1 was studied in rat hippocampal slices. Tetanization of either the alveus or stratum oriens produced > 30min depression of the radiatum field EPSP and population spike, but generally only in the presence of picrotoxin. The spike depression was accounted for by the EPSP depression, and could be blocked by prior administration of anN-methyl-d-aspartate receptor antagonist. These data suggest that the induction of non-associative LTD is depolarization-dependent and involves theN-methyl-d-aspartate receptor/channel complex.     

Nicotine accelerates reversal of long-term potentiation and enhances long-term depression in the rat hippocampal CA1 region

In the hippocampal CA1 region, low-frequency stimulation (LFS; 200 pulses at 1 Hz) causes reversal of long-term potentiation (depotentiation, DP) and long-term depression (LTD), both of which are thought to be the cellular substrate of learning and memory. Because nicotine enhances learning and memory, we examined if nicotine modulates DP and LTD in the hippocampal CA1 region. Bath application of nicotine during LFS accelerated DP, that is, potentiated synaptic responses in hippocampal CA1 neurons returned to pre-tetanic control levels more rapidly in the presence of nicotine. Because a similar acceleration of DP was observed using the alpha7 nicotinic acetylcholine receptor (nAChR)-selective antagonist methyllcaconitine (MLA), the nicotine effect appeared to be at least partly mediated by nicotine-induced desensitization of alpha7 nAChRs. Delivery of LFS in the presence of nicotine or MLA also depressed synaptic responses in a naive pathway and facilitated LTD, that is, the magnitude of LTD was larger when the drug was present during LFS. Thus, these results demonstrate that nicotine facilitates DP and LTD, which may represent, at least in part, the cellular mechanism underlying nicotine-induced cognitive enhancement.