Prior short-term synaptic disinhibition facilitates long-term potentiation and suppresses long-term depression at CA1 hippocampal synapses

Long-term potentiation (LTP) and long-term depression (LTD) are two main forms of activity-dependent synaptic plasticity that have been extensively studied as the putative mechanisms underlying learning and memory. Current studies have demonstrated that prior synaptic activity can influence the subsequent induction of LTP and LTD at Schaffer collateral-CA1 synapses. Here, we show that prior short-term synaptic disinhibition induced by type A gamma-aminobutyric acid (GABA) receptor antagonist picrotoxin exhibited a facilitation of LTP induction and an inhibition of LTD induction. This effect lasted between 10 and 30 min after washout of picrotoxin and was specifically inhibited by the L-type voltage-operated Ca2+ channel (VOCC) blocker nimodipine, but not by the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphopentanoic acid (D-APV). Moreover, this picrotoxin-induced priming effect was mimicked by forskolin, an activator of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), and was blocked by the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 22536) and the PKA inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate (Rp-cAMPS). It was also found that following picrotoxin application, CA1 neurons have a higher probability of synchronous discharge in response to a population of excitatory postsynaptic potential (EPSP) of fixed slope (EPSP/spike potentiation). However, picrotoxin treatment did not significantly affect paired-pulse facilitation (PPF). These findings suggest that a brief of GABAergic disinhibition can act as a priming stimulus for the subsequent induction of LTP and LTD at Schaffer collateral-CA1 synapses. The increase in Ca2+ influx through L-type VOCCs in turn triggering a cAMP/PKA signalling pathway is a possible molecular mechanism underlying this priming effect.     

Augmentation of LTP induced by Primed–Bursts tetanic stimulation in hippocampal CA1 area of morphine dependent rats

The effects of chronic morphine administration on the development of Long-term potentiation (LTP) were investigated at the Schaffer collateral-CA1 pyramidal cell synapses of the rat hippocampal slices using primed-bursts tetanic stimulation. Significant enhancement of orthodromic population spike (OPS) was found for all stimulus intensities after tetanic stimulation. OPS enhancement was greatest when tested with low to mid-range stimulus intensities (25 and 50 μA). There was also significant decrease in OPS delay. These responses were similar in slices from both control and morphine dependent rats. At all delivered stimulus intensities, the amount of LTP of OPS in slices from dependent rats was larger than that of control slices. However, these differences in LTP of OPS were significant at low stimulus intensities. These findings suggest that chronic morphine administration had induced changes in CA1 neurocircuitry which modulated synaptic plasticity during high frequency stimulation and appeared as augmented LTP.     

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.     

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.     

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.     

Potassium-induced long-term potentiation in rat hippocampal slices

We observed that a transient increase in extracellular potassium concentration (50 mM for 40 s) was sufficient to induce long-term potentiation (LTP) of synaptic transmission in area CA1 of the hippocampal slice. Potassium-induced potentiation of the Schaffer collateral/commissural synapses demonstrated several features characteristic of tetanus-induced LTP: (1) population excitatory post-synaptic potential (EPSP) amplitudes were enhanced to a similar magnitude (on average 70% above baseline) which (2) lasted for more than 20 min; (3) induction was blocked by bath application of the specific N-methyl-d-aspartate (NMDA) receptor antagonistd-2-amino-5-phosphonovalerate (d-APV), and (4) was attenuated by reduction of the concentration of calcium in the extracellular medium. Induction of either potassium-induced LTP or tetanus-induced LTP occluded the subsequent expression of the other. Finally, exposure to high potassium in the absence of electrical stimulation was sufficient to induce LTP. Taken together, these data indicate that brief depolarizing stimuli other than tetanus can induce LTP. Because potassium-induced LTP is not restricted to the subset of afferents examined electrophysiologically, such a method could facilitate analyses of the biochemical events underlying both the induction and expression of LTP.     

Input- and subunit-specific AMPA receptor trafficking underlying long-term potentiation at hippocampal CA3 synapses

Hippocampal CA3 pyramidal neurons receive synaptic inputs from both mossy fibres (MFs) and associational fibres (AFs). Long-term potentiation (LTP) at these synapses differs in its induction sites and N-methyl-D-aspartate receptor (NMDAR) dependence. Most evidence favours the presynaptic and postsynaptic mechanisms for induction of MF LTP and AF LTP, respectively. This implies that molecular and functional properties differ between MF and AF synapses at both presynaptic and postsynaptic sites. In this study, we focused on the difference in the postsynaptic trafficking of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) between these synapses. To trace the subunit-specific trafficking of AMPARs at each synapse, GluR1 and GluR2 subunits were introduced into CA3 pyramidal neurons in hippocampal organotypic cultures using the Sindbis viral expression system. The electrophysiologically-tagged GluR2 AMPARs, produced by the viral-mediated transfer of the unedited form of GluR2 (GluR2Q), were inserted into both MF and AF postsynaptic sites in a neuronal activity-independent manner. Endogenous Ca(2+)-impermeable AMPARs at these synapses were replaced with exogenous Ca(2+)-permeable receptors, and Ca(2+) influx via the newly expressed postsynaptic AMPARs induced NMDAR-independent LTP at AF synapses. In contrast, no GluR1 AMPAR produced by the gene transfer was constitutively incorporated into AF postsynaptic sites, and only a small amount into MF postsynaptic sites. The synaptic trafficking of GluR1 AMPARs was triggered by the activity of Ca(2+)/calmodulin-dependent kinase II or high-frequency stimulation to induce LTP at AF synapses, but not at MF synapses. These results indicate that MF and AF postsynaptic sites possess distinct properties for AMPAR trafficking in CA3 pyramidal neurons.     

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.     

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.     

Spatiotemporal visualization of long-term potentiation and depression in the hippocampal CA1 area

Long-term potentiation (LTP) in the CA1 area of the hippocampus depends critically on the statistical characteristics of its stimulus. The ability of optical imaging to record spatial distribution has made it possible to examine systematically the effect of higher-order statistical characteristics, such as the correlation between successive pairs of inter-stimulus intervals (ISIs) on the induction of LTP. Therefore, the function of frequency (first-order) and temporal pattern (second-order) was examined using this imaging technique. To investigate the dependence of LTP on frequency, periodic stimuli with the same number of pulses were applied at different frequencies (1-10 Hz, n=200) to Schaffer commissural-collateral fibers. While stimulus frequencies from 2-10 Hz induced LTP of varying magnitudes and low-frequency stimuli (1 Hz) induced long-term depression (LTD), spatial distribution remained consistent. These results suggest that induction frequency has a greater effect on the magnitude of LTP than on its spatial distribution. By employing nonperiodic stimuli at the same mean frequency (2 Hz), the effect of varying the temporal structure of a stimulus was also investigated. As the correlation of successive ISIs was increased from negative to positive, not only did the magnitude of LTP increase, there was also a statistically significant change in the spatial distribution of LTP. Interestingly, when a strong negatively correlated stimulus was applied, both LTP and LTD were simultaneously observed in the CA1 area. It was also found that the magnitude of LTP 200-300 mum distal to the cellular layer was larger than that of the LTP induced proximal (<100 microm) to that layer. These results support the hypothesis that the spatial distribution of LTP throughout the hippocampus relies principally on the temporal patterning of input stimulation. This insight into the structure of the CA1 neural network may reveal the importance of stimulus timing events in the spatial encoding of memories.     

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.     

Chronic exposure to environmental levels of lead impairs in vivo induction of long-term potentiation in rat hippocampal dentate

This study examined the effects of chronic developmental lead (Pb) exposure in rats on hippocampal long-term potentiation (LTP). Male offspring were exposed to 0.2% Pb acetate continuously from birth until testing at 85–105 days. Excitatory postsynaptic potential (EPSP) and population spike amplitudes were measured in the dentate hilar region in response to stimulation applied to the lateral perforant path. LTP was induced in control animals with an average maximal EPSP potentiation of 41%, which was significantly greater than the increase in EPSP amplitudes (2%) in exposed animals after tetanizing stimulation. Current-voltage curves in controls demonstrated significant increases in EPSPs and population spikes after application of pulse trains to induce LTP, while exposed rats exhibited no discernible change in responses. These findings suggest that induction or development of LTP in the dentate hilar region in vivo is impaired by chronic developmental exposure to environmentally relevant levels of Pb.     

Dependence on morphine impairs the induction of long-term potentiation in the CA1 region of rat hippocampal slices

The effect of chronic morphine treatment on hippocampal CA1-long-term potentiation (LTP) was examined in vitro. The field excitatory postsynaptic potential (fEPSP) was recorded from stratum radiatum of area CA1 following stimulation of Schaffer collaterals in slices taken from control and morphine-dependent rats. To induce LTP, a 100-Hz primed burst stimulation (PBs) was used. Slices from rats exposed to chronic morphine showed no effect on baseline synaptic responses. Slices from control rats or rats exposed to chronic morphine maintained in ACSF with either morphine or naloxone also had no effect on baseline synaptic responses. Control slices perfused with medium containing either morphine or naloxone as well as both drugs exhibited hippocampal CA1 LTP. Similarly, slices from morphine-dependent rats maintained in ACSF with either naloxone or just morphine free ACSF also exhibited hippocampal CA1 LTP. However, slices from morphine-dependent rats maintained in ACSF with morphine significantly attenuated hippocampal CA1 LTP. These findings suggest that hippocampal CA1-LTP can still be achieved in slices from morphine-dependent rats exhibiting morphine withdrawal through mechanisms that may be inhibited by opiate exposure. Such studies can be helpful in understanding the neurophysiological substrate of memory deficits seen in opiate addicts.     

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.     

Emergence of NMDAR-independent long-term potentiation at hippocampal CA1 synapses following early adolescent exposure to chronic intermittent ethanol: role for sigma-receptors

Adolescent humans who abuse alcohol are more vulnerable than adults to the development of memory impairments. Memory impairments often involve modifications in the ability of hippocampal neurons to establish long-term potentiation (LTP) of excitatory neurotransmission; however, few studies have examined how chronic ethanol exposure during adolescence affects LTP mechanisms in hippocampus. We investigated changes in LTP mechanisms in hippocamal slices from rats exposed to intoxicating concentrations of chronic intermittent ethanol (CIE) vapors in their period of early-adolescent (i.e., prepubescent) or late-adolescent (i.e., postpubescent) development. LTP was evaluated at excitatory CA1 synapses in hippocampal slices at 24 h after the cessation of air (control) or CIE vapor treatments. CA1 synapses in control slices showed steady LTP following induction by high-frequency stimulation, which was fully dependent on NMDAR function. By contrast, slices from early-adolescent CIE exposed animals showed a compound form of LTP consisting of an NMDAR-dependent component and a slow-developing component independent of NMDARs. These components summated to yield LTP of robust magnitude above LTP levels in age-matched control slices. Bath-application of the sigma-receptor antagonist BD1047 and the neuroactive steroid pregnenolone sulfate, but not acute ethanol application, blocked NMDAR-independent LTP, while leaving NMDAR-dependent LTP intact. Analysis of presynaptic function during NMDAR-independent LTP induction demonstrated increased presynaptic function via a sigma-receptor-dependent mechanism in slices from early-adolescent CIE-exposed animals. By contrast, CIE exposure after puberty onset in late-adolescent animals produced decrements in LTP levels. The identification of a role for sigma-receptors and neuroactive steroids in the development of NMDAR-independent LTP suggests an important pathway by which hippocampal synaptic plasticity, and perhaps memory, may be uniquely altered by chronic ethanol exposure during the prepubescent phase of adolescent development.     

Steroid pregnenolone sulfate enhances NMDA-receptor-independent long-term potentiation at hippocampal CA1 synapses: role for L-type calcium channels and sigma-receptors

Severe stress elevates plasma and CNS levels of endogenous neuroactive steroids that can contribute to the influence of stress on memory formation. Among the neuroactive steroids, pregnenolone sulfate (PREGS) reportedly strengthens memories and is readily available as a memory-enhancing supplement. PREGS actions on memory may reflect its ability to produce changes in memory-related neuronal circuits, such as long-term potentiation (LTP) of excitatory transmission in hippocampus. Here, we report a previously undiscovered pathway by which PREGS exposure promotes activity-dependent LTP of field excitatory postsynaptic potentials at CA1 synapses in hippocampal slices. Thus, application of PREGS, but not the phosphated conjugate of the steroid, selectively facilitates the induction of a slow-developing LTP in response to high-frequency (100 Hz) afferent stimulation, which is not induced in the absence of the steroid. The slow-developing LTP is independent of NMDA-receptor function (i.e., dAP5 insensitive) but dependent on functional L-type voltage-gated calcium channels (VGCC) and sigma-receptors. By contrast, PREGS at the highest concentration tested produces a depression in NMDA-receptor-dependent LTP, which is evident when sigma-receptor function is compromised by the presence of a sigma-receptor antagonist. We found that at early times during the induction phase of L-type VGCC-dependent LTP, PREGS via sigma-receptors transiently enhances presynaptic function. As well, during the maintenance phase of L-type VGCC-dependent LTP, PREGS promotes a further increase in presynaptic function downstream of LTP induction, as evidenced by a decrease in paired-pulse facilitation. The identification of complex regulatory actions of PREGS on LTP, involving sigma-receptors, L-type VGCCs, NMDA-receptors, and inhibitory circuits will aid future research endeavors aimed at understanding the precise mechanisms by which this stress-associated steroid may engage multiple LTP-signaling pathways that alter synaptic transmission at memory-related synapses.     

Perforant pathway-evoked long-term potentiation of CA1 neurons in the hippocampal slice preparation

Previously, we have presented electrophysiological evidence reaffirming the existence of a controversial hippocampal pathway. These fibers are part of the perforant pathway and terminate directly on the CA1 cells. We now report that, in the hippocampal slice preparation, tetanic stimulation of the perforant pathway produces long-term potentiation (LTP) of CA1 cell responses. LTP of population spikes varied from 150% to 500%. The results were of interest because these axons synapse at distal sites on the apical dendrite. This location is usually thought to be a difficult site to evoke action potentials.     

Homosynaptic long-term depression of CA3–CA3 synapses in the in vivo hippocampus

We tested the hypothesis that homosynaptic long-term depression (LTD) can be induced at the CA3–CA3 synapses in the adult, in vivo hippocampus while the CA3–CA1 synapses remain unchanged. Low-frequency conditioning stimulation of the contralateral fimbria significantly depressed the CA3 population response but did not change the simultaneously recorded CA3 response to angular bundle test stimulation. Similarly, in another group of animals, low-frequency conditioning stimulation of the contralateral fimbria depressed the CA3 synaptic response and left the collateral CA1 synaptic response unchanged. Among the possible explanations for this differential induction of homosynaptic LTD at the CA3–CA3 and CA3–CA1 synapses are differential control of intracellular calcium, differing levels of inhibition in these two regions, and the recency of `natural' long-term potentiation in the two regions.     

An in vivo model for investigating bilateral synaptic plasticity across CA3/CA1 synapses in guinea pig dorsal hippocampus

A method is described for concurrent investigation of long-term potentiation (LTP) in the left and right CA1 synapses in dorsal hippocampi in guinea pig in vivo. Briefly, animals are anesthetized with urethane, and small access holes are made in the skull through which electrodes are lowered to stimulate the left CA3 and record from both CA1 regions. Using this animal model, we have found that LTP is produced in both CA1 regions, following conditioning stimulation to the left CA3. However, in some animals LTP occurred in the left CA1 without concomitant synaptic potentiation in the contralateral CA1. We also observed that in some experiments synaptic potentiation in the contralateral CA1, when present, decayed to baseline levels even though LTP persisted in the ipsilateral CA1. To conclude, our data on bilateral LTP demonstrates findings that are best addressed in vivo.