Induction Of Long-term Potentiation In CA1 Research Articles

Influx of extracellular Zn(2+) into the hippocampal CA1 neurons is required for cognitive performance via long-term potentiation.

Physiological significance of synaptic Zn(2+) signaling was examined in the CA1 of young rats. In vivo CA1 long-term potentiation (LTP) was induced using a recording electrode attached to a microdialysis probe and the recording region was locally perfused with artificial cerebrospinal fluid (ACSF) via the microdialysis probe. In vivo CA1 LTP was inhibited under perfusion with CaEDTA and ZnAF-2DA, extracellular and intracellular Zn(2+) chelators, respectively, suggesting that the influx of extracellular Zn(2+) is required for in vivo CA1 LTP induction. The increase in intracellular Zn(2+) was chelated with intracellular ZnAF-2 in the CA1 1h after local injection of ZnAF-2DA into the CA1, suggesting that intracellular Zn(2+) signaling induced during learning is blocked with intracellular ZnAF-2 when the learning was performed 1h after ZnAF-2DA injection. Object recognition was affected when training of object recognition test was performed 1h after ZnAF-2DA injection. These data suggest that intracellular Zn(2+) signaling in the CA1 is required for object recognition memory via LTP. Surprisingly, in vivo CA1 LTP was affected under perfusion with 0.1-1μM ZnCl2, unlike the previous data that in vitro CA1 LTP was enhanced in the presence of 1-5μM ZnCl2. The influx of extracellular Zn(2+) into CA1 pyramidal cells has bidirectional action in CA1 LTP. The present study indicates that the degree of extracellular Zn(2+) influx into CA1 neurons is critical for LTP and cognitive performance.

Functional optical probing of the hippocampal trisynaptic circuit in vitro: network dynamics, filter properties, and polysynaptic induction of CA1 LTP.

Decades of brain research have identified various parallel loops linking the hippocampus with neocortical areas, enabling the acquisition of spatial and episodic memories. Especially the hippocampal trisynaptic circuit [entorhinal cortex layer II → dentate gyrus (DG) → cornu ammonis (CA)-3 → CA1] was studied in great detail because of its seemingly simple connectivity and characteristic structures that are experimentally well accessible. While numerous researchers focused on functional aspects, obtained from a limited number of cells in distinct hippocampal subregions, little is known about the neuronal network dynamics which drive information across multiple synapses for subsequent long-term storage. Fast voltage-sensitive dye imaging in vitro allows real-time recording of activity patterns in large/meso-scale neuronal networks with high spatial resolution. In this way, we recently found that entorhinal theta-frequency input to the DG most effectively passes filter mechanisms of the trisynaptic circuit network, generating activity waves which propagate across the entire DG-CA axis. These “trisynaptic circuit waves” involve high-frequency firing of CA3 pyramidal neurons, leading to a rapid induction of classical NMDA receptor-dependent long-term potentiation (LTP) at CA3-CA1 synapses (CA1 LTP). CA1 LTP has been substantially evidenced to be essential for some forms of explicit learning in mammals. Here, we review data with particular reference to whole network-level approaches, illustrating how activity propagation can take place within the trisynaptic circuit to drive formation of CA1 LTP.

Ventral tegmental area inactivation suppresses the expression of CA1 long term potentiation in anesthetized rat.

The hippocampus receives dopaminergic projections from the ventral tegmental area (VTA). Modulatory effect of dopamine on hippocampal long term potentiation (LTP) has been studied before, but there are conflicting results and some limitations in previous reports. Most of these studies show a significant effect of dopamine on the late phase of LTP in CA1 area of the hippocampus, while few reports show an effect on the early phase. Moreover, they generally manipulated dopamine receptors in the hippocampus and there are few studies investigating influence of the VTA neural activity on hippocampal LTP in the intact brain. Besides, VTA neurons contain other neurotransmitters such as glutamate and GABA that may modify the net effect of dopamine. In this study we examined the effect of VTA reversible inactivation on the induction and maintenance of early LTP in the CA1 area of anesthetized rats, and also on different phases of learning of a passive avoidance (PA) task. We found that inactivation of the VTA by lidocaine had no effect on CA1 LTP induction and paired-pulse facilitation, but its inactivation immediately after tetanic stimulation transiently suppressed the expression of LTP. Blockade of the VTA 20 min after tetanic stimulation had no effect on the magnitude of LTP. Moreover, VTA inactivation immediately after training impaired memory in the passive avoidance task, while its blockade before or 20 min after training produced no memory deficit. It can be concluded that VTA activity has no effect on CA1 LTP induction and acquisition of PA task, but involves in the expression of LTP and PA memory consolidation.

Xenon Attenuates Hippocampal Long-term Potentiation by Diminishing Synaptic and Extrasynaptic N -methyl-D-aspartate Receptor Currents

The memory-blocking properties of general anesthetics are of high clinical relevance and scientific interest. The inhalational anesthetic xenon antagonizes N-methyl-D-aspartate (NMDA) receptors. It is unknown if xenon affects long-term potentiation (LTP), a cellular correlate for memory formation. In hippocampal brain slices, the authors investigated in area CA1 whether xenon affects LTP, NMDA receptor-mediated neurotransmission, and intracellular calcium concentrations. In sagittal murine hippocampal brain slices, the authors investigated the effects of xenon on LTP by recording excitatory postsynaptic field potentials. Using fluorometric calcium imaging, the authors tested the influence of xenon on calcium influx during high-frequency stimulation. In addition, using the patch-clamp technique, the xenon effect on synaptic and extrasynaptic NMDA receptors and L-type calcium channels was examined. In the absence of xenon, high-frequency stimulation reliably induced LTP and potentiated field potential slopes to (mean ± SEM) 127.2 ± 5.8% (P < 0.001). In the presence of xenon, high-frequency stimulation induced only a short-term potentiation, and field potentials returned to baseline level after 15-20 min (105.9 ± 2.9%; P = 0.090). NMDA receptor-mediated excitatory postsynaptic currents were reduced reversibly by xenon to 65.9 ± 9.4% (P = 0.007) of control. When extrasynaptic receptors were activated, xenon decreased NMDA currents to 58.2 ± 5.8% (P < 0.001). Xenon reduced the increase in intracellular calcium during high-frequency stimulation without affecting L-type calcium channels. N-methyl-D-aspartate receptor activation is crucial for the induction of CA1 LTP. Thus, the depression of NMDA receptor-mediated neurotransmission presumably contributes to the blockade of LTP under xenon. Because LTP is assumed to be involved in learning and memory, its blockade might be a key mechanism for xenon's amnestic properties.

Entorhinal theta-frequency input to the dentate gyrus trisynaptically evokes hippocampal CA1 LTP

There exists substantial evidence that some forms of explicit learning in mammals require long-term potentiation (LTP) at hippocampal CA3-CA1 synapses. While CA1 LTP has been well characterized at the monosynaptic level, it still remains unclear how the afferent systems to the hippocampus can initiate formation of this neuroplastic phenomenon. Using voltage-sensitive dye imaging (VSDI) in a mouse brain slice preparation, we show that evoked entorhinal cortical (EC) theta-frequency input to the dentate gyrus highly effectively generates waves of neuronal activity which propagate through the entire trisynaptic circuit of the hippocampus (“HTC-Waves”). This flow of activity, which we also demonstrate in vivo, critically depends on frequency facilitation of mossy fiber to CA3 synaptic transmission. The HTC-Waves are rapidly boosted by the cognitive enhancer caffeine (5 μM) and the stress hormone corticosterone (100 nM). They precisely follow the rhythm of the EC input, involve high-frequency firing (>100 Hz) of CA3 pyramidal neurons, and induce NMDA receptor-dependent CA1 LTP within a few seconds. Our study provides the first experimental evidence that synchronous theta-rhythmical spiking of EC stellate cells, as occurring during EC theta oscillations, has the capacity to drive induction of CA1 LTP via the hippocampal trisynaptic pathway. Moreover, we present data pointing to a basic filter mechanism of the hippocampus regarding EC inputs and describe a methodology to reveal alterations in the “input–output relationship” of the hippocampal trisynaptic circuit.

Involvement of N‐methyl‐D‐aspartate receptor subunits in zinc‐mediated modification of CA1 long‐term potentiation in the developing hippocampus

Zinc is an endogenous N-methyl-D-aspartate (NMDA) receptor blocker. It is possible that zinc-mediated modification of hippocampal CA1 long-term potentiation (LTP) is linked to the expression of NMDA receptor subunits, which varies with postnatal development. In the present study, the effect of ZnCl(2) and CaEDTA, a membrane-impermeable zinc chelator, on CA1 LTP induction was examined in hippocampal slices from immature (3-week-old) and young (6-week-old) rats. Tetanus (10-100 Hz, 1 sec)-induced CA1 LTP was more greatly enhanced in 3-week-old rats. CA1 LTP was inhibited in the presence of 2-amino-5-phosphonovalerate (APV), an NMDA receptor antagonist, and CaEDTA in 3-week-old rats, as in the case of 6-week-old rats reported previously. In 3-week-old rats, on the other hand, 5 μM ZnCl(2) attenuated NMDA receptor-mediated EPSPs more than in 6-week-old rats and significantly attenuated CA1 LTP. Moreover, 5 μM ZnCl(2) significantly attenuated CA1 LTP in the presence of (2R,4S)-4-(3-phosphonopropyl)-2-piperidinecarboxylic acid (PPPA), an NR2A antagonist, in 3-week-old rats, but not that in the presence of ifenprodil, an NR2B antagonist, suggesting that zinc-mediated attenuation of CA1 LTP is associated with the preferential expression of NR2B subunit in 3-week-old rats. In 6-week-old rats, however, 5 μM ZnCl(2) significantly potentiated CA1 LTP and also CA1 LTP in the presence of PPPA. The present study demonstrates that endogenous zinc may participate in the induction of CA1 LTP. It is likely that the changes in expression of NMDA receptor subunits are involved in the zinc-mediated modification of CA1 LTP in the developing hippocampus.

Differential effects of zinc influx via AMPA/kainate receptor activation on subsequent induction of hippocampal CA1 LTP components

Zinc potentiates the induction of NMDA receptor-dependent hippocampal CA1 long-term potentiation (LTP) at low micromolar concentrations, while excessive zinc attenuates it. Homeostasis of synaptic zinc is critical for LTP induction. In the present study, LTP at hippocampal CA1 synapses was analyzed focused on the timing and level of zinc influx into hippocampal cells in hippocampal slices from young rats. Zinc (100 μM) perfusion increased intracellular zinc level and subsequently attenuated CA1 LTP induced by tetanic stimuli at 100 Hz for 1 s, which was completely inhibited in the presence of 50 μM APV, an NMDA receptor antagonist. When 10 μM CNQX, an AMPA/kainate receptor antagonist, which reduced zinc influx into hippocampal cells, was perfused prior to the zinc perfusion, the attenuation of CA1 LTP by the zinc perfusion was restored. These results suggest that facilitated zinc influx into hippocampal cells via AMPA/kainate receptor activation is an event to attenuate subsequent induction of NMDA receptor-dependent CA1 LTP. On the other hand, the zinc pre-perfusion also attenuated CA1 LTP induced by 200-Hz tetanus, but not NMDA receptor-independent CA1 LTP induced by 200-Hz tetanus in the presence of APV, suggesting that the induction of NMDA receptor-independent CA1 LTP is less susceptibility to the facilitated zinc influx into hippocampal CA1 cells. Zinc influx via AMPA/kainate receptor activation may differentially act on subsequent induction of CA1 LTP components.

Positive modulation of long-term potentiation at hippocampal CA1 synapses by low micromolar concentrations of zinc

The role of zinc, an endogenous N-methyl-d-aspartate (NMDA) receptor antagonist, in long-term potentiation (LTP) at hippocampal CA1 synapses is poorly understood. In the present study, the effect of exogenous zinc and zinc chelators on CA1 LTP was examined by using hippocampal slices from rats. CA1 LTP after tetanic stimulation (100 Hz, 1 s) was potentiated in the presence of 5 μM ZnCl2, but not in the presence of 30 μM. In varying the frequency (10–100 Hz, 1 s), zinc (5 μM) caused a significant shift of the frequency-response curve and lowered the threshold in LTP induction. The present study is the first to demonstrate that CA1 LTP is potentiated by low micromolar concentrations of zinc. Endogenous zinc is likely to reach low micromolar concentrations in the extracellular compartment in CA1 LTP induction. On the other hand, zinc has no effect on field excitatory postsynaptic potentials (fEPSPs) after tetanic stimulation in the presence of 2-amino-5-phosphonovalerate (APV), an NMDA receptor antagonist, in which LTP was abolished, indicating that NMDA receptor activation is necessary for the potentiation of CA1 LTP by zinc. The pretreatment with ZnAF-2DA, a membrane-permeable zinc chelator, which was used to block the increase in intracellular Zn2+, inhibited LTP and also LTP potentiated by zinc. It is likely that Zn2+ taken up during LTP induction potentiates CA1 LTP via NMDA receptor activation.

Reparatory effects of nicotine on NMDA receptor‐mediated synaptic plasticity in the hippocampal CA1 region of chronically lead‐exposed rats

Activation of neuronal nicotinic acetylcholine receptors (nAChRs) modulates the induction of long-term potentiation (LTP): a possible cellular mechanism of learning. To investigate the effect of nicotine on synaptic plasticity in chronically lead-exposed rats, field excitatory postsynaptic potentials and paired-pulse facilitation (PPF) were recorded in the CA1 area of hippocampal slices from chronically lead-exposed 23-30-day-old rats. The results showed the following. (1) Nicotine (1 microm) facilitated the induction of LTP in CA1 by a weak tetanic stimulation (100 Hz, 20 pulses), which does not by itself produce LTP in lead-exposed rats. This effect was significantly suppressed by mecamylamine, a nicotinic antagonist, suggesting that the facilitation of LTP was through nAChRs. (2) The nicotine-facilitated LTP was blocked by dihydro-beta-erythroidine (DHbetaE), a non-alpha7 nAChR antagonist, whereas long-term depression (LTD) was produced by the combination of nicotine and methyllycaconitine, a alpha7-nAChR antagonist. This type of LTD was blocked by DHbetaE. This suggested that several nAChR subtypes were involved in the nicotine-facilitated synaptic plasticity. (3) Nicotine enhanced PPF in the hippocampal CA1 region, and the nicotine-facilitated LTP in lead-exposed rats was blocked by either d-(-)-2-amino-5-phosphonopentanoic acid, the N-methyl-d-aspartate (NMDA) receptor antagonist, or picrotoxin, an antagonist of gamma-aminobutyric acid(A) receptors. We suggest that nicotine-facilitated synaptic plasticity was due to the activation of NMDARs by disinhibition of pyramidal cells through presynaptic nAChRs. This may represent the cellular basis of nicotine-facilitated cognitive enhancement observed in chronically lead-exposed rats.

Neonatal isolation accelerates the developmental switch in the signalling cascades for long‐term potentiation induction

The molecular mechanisms underlying long-term potentiation (LTP) in the CA1 region of the hippocampus are known to vary with developmental age. The physiological factors regulating this developmental change, however, have not yet been elucidated. Here we show that mild neonatal isolation accelerates the developmental switch in the signalling cascades for hippocampal CA1 LTP induction from a cyclic AMP-dependent protein kinase (PKA)- to a Ca2(+)/calmodulin-dependent protein kinase II (CaMKII)-dependent pattern via the activation of the corticotrophin-releasing factor (CRF) system. Furthermore, this action appears to be mediated through an increased transcription of the alpha isoform of the CaMKII (CaMKIIalpha) gene. We also demonstrate that application of CRF to cultured hippocampal neurones significantly increases the expression of CaMKIIalpha, which is blocked by the non-specific CRF receptor antagonist astressin, the specific CRF receptor 1 antagonist NBI 27911, and the PKA inhibitor KT5720, but not by the CRF receptor 2 antagonist K 41498, or the protein kinase C inhibitor, bisindolylmaleimide I. CRF signalling also mediates the normal maturation of LTP. These results suggest a novel role for CRF in regulating early developmental events in the hippocampus, and indicate that, although maternal deprivation is stressful for the neonate, appropriate neonatal isolation can serve to promote an endocrine state that fosters the rate of maturation of the signalling cascades underlying the induction of LTP in the developing hippocampus.

Single cell analysis of activity-dependent cyclic AMP-responsive element-binding protein phosphorylation during long-lasting long-term potentiation in area CA1 of mature rat hippocampal-organotypic cultures

Phosphorylation of the transcription factor cyclic AMP (cAMP)-response element-binding protein (CREB) has been implicated in long-term synaptic plasticity and memory, and its activation has been proposed to be required for the maintenance of long-term potentiation (LTP). The previously described temporal dynamics of CREB phosphorylation during the maintenance of LTP showed differences between experimental models. In the present study the level of CREB phosphorylation was evaluated in organotypic hippocampal slices from young adult rats (P25-30) after long-lasting LTP was induced. Immunohistochemistry and confocal imaging were used to determine the ratio between non-phosphorylated and phosphorylated CREB at a single cell resolution, revealing not only the temporal dynamics but also the extent of CREB phosphorylation. The activation of CREB after LTP-induction was compared with cAMP-activation after bath application of forskolin. An increase in cAMP by forskolin resulted in a persistent, uniform increase of the phosphorylated CREB (pCREB/CREB immunofluorescence ratio) in all hippocampal principal neurons. In contrast, the induction of long-lasting LTP in CA1 was accompanied by a local increase in the pCREB/CREB ratio. Both CREB activation and LTP induction in mature cultured slices required N-methyl- d-aspartate (NMDA) receptor activation. CREB phosphorylation continued to increase for 4 h during LTP maintenance. This sustained activation is in contrast to previous observations in acutely prepared slices and supports the hypothesis that CREB plays an important role during the late phases of LTP.

(+)-MCPG blocks induction of LTP in CA1 of rat hippocampus via agonist action at an mGluR group II receptor.

We investigated the effect of metabotropic glutamate receptor (mGluR) ligands on the induction of long-term potentiation (LTP) of field excitatory postsynaptic potentials (EPSPs) in CA1 of rat hippocampus, in particular the manner by which the nonsubtype selective mGluR ligand alpha-methyl-4-carboxyphenylglycine [(+)-MCPG] blocks LTP induction. Normalized control LTP was blocked by (+)-MCPG (250 microM), but not by the mGluRI selective antagonist (S)-4-carboxyphenylglycine (4-CPG), the mGluRII selective antagonist 1/(2S,3S, 4S)-2-methyl-2-(carboxycyclopropyl) glycine (MCCG), or the mGluRIII antagonist (S)-2-amino-2-methyl-4-phosphonobutanoic acid/alpha-methyl (MAP4). In contrast the mGluRII agonist ((1S, 3S)-1-aminocyclopentante-1,3-dicarboxylic acid -(1S,3S)-ACPD-; 10 or 25 microM) completely and consistently blocked LTP. The block of LTP by both (1S,3S)-ACPD and (+)-MCPG could be prevented by preincubation with the mGluRII antagonist MCCG. These studies demonstrate that (+)-MCPG blocks LTP induction through an agonist action at an mGluRII receptor and not through a nonselective antagonist action.

Contributions of AMPA and GABA A receptors to the induction of NMDAR-dependent LTP in CA1

The contributions of (±)-a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and g-aminobutyric acid (GABA A) receptors in the induction of long-term potentiation (LTP) have been studied in the CA1 region of the rat hippocampus. The results suggest that: (1) in physiological conditions, AMPARs are necessary for the induction of N-methyl- d-aspartate receptor (NMDAR)-dependent LTP since LTP cannot be elicited in the presence of the AMPAR antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Although a NMDAR-dependent LTP occurs in the presence of a GABA A antagonist and high concentrations of divalents cations, blockade of AMPARs leads to a voltage-dependent calcium channels (VDCC)-dependent LTP since its induction is blocked by nifedipine and not by APV. (2) The bicarbonate-induced GABA A receptor-mediated depolarizing response is not necessary in the induction of NMDAR-dependent or VDCC-dependent LTP since induction of these two types of LTP were not blocked by acetazolamide or in a nominally bicarbonate-free solution.

Reduced hippocampal in vitro CA1 long-term potentiation in rat offsprings with increased circulating corticosterone during neonatal life

A moderate increase in plasma level of corticosterone was induced in dams by adding the hormone (200 μ/ml) to the drinking water from the day after delivery to weaning. This procedure produces a parallel increase in plasma levels of the hormone in the pups (from 0.7 ± 0.1 to 1.2 ± 0.2 μg/100 ml) at 10 days of lactation. A significant ( P < 0.01) reduction in the magnitude of the long-term potentiation (LTP) of the CA1 population spike occurred in hippocampal slices obtained from 30–45 day old male corticosterone-nursed rats with respect to controls, while no significant difference occurred in the magnitude of the basal CA1 evoked extracellular somatic field potentials with respect to controls. The results demonstrate that a moderate increase in plasma corticosterone during neonatal life, obtained through miternal milk, has long-lasting effects on the hippocampal CA1 synaptic plasticity. In addition, these results together with our previous findings [Catalani, A. et al., Brain Res., 624 (1993) 209–215], demonstrating that 30 day old corticosterone-nursed offsprings perform better than controls in the place learning version of the Morris water maze, show no relationships between in vitro CA1 LTP induction and spatial learning in agreement with literature data.

Reduced hippocampal in vitro CA1 long-term potentiation in rat offsprings with increased circulating corticosterone during neonatal life

A moderate increase in plasma level of corticosterone was induced in dams by adding the hormone (200 μ/ml) to the drinking water from the day after delivery to weaning. This procedure produces a parallel increase in plasma levels of the hormone in the pups (from 0.7 ± 0.1 to 1.2 ± 0.2 μg/100 ml) at 10 days of lactation. A significant ( P < 0.01) reduction in the magnitude of the long-term potentiation (LTP) of the CA1 population spike occurred in hippocampal slices obtained from 30–45 day old male corticosterone-nursed rats with respect to controls, while no significant difference occurred in the magnitude of the basal CA1 evoked extracellular somatic field potentials with respect to controls. The results demonstrate that a moderate increase in plasma corticosterone during neonatal life, obtained through miternal milk, has long-lasting effects on the hippocampal CA1 synaptic plasticity. In addition, these results together with our previous findings [Catalani, A. et al., Brain Res., 624 (1993) 209–215], demonstrating that 30 day old corticosterone-nursed offsprings perform better than controls in the place learning version of the Morris water maze, show no relationships between in vitro CA1 LTP induction and spatial learning in agreement with literature data.

Head direction cells recorded in the anterior thalamic nuclei of freely moving rats

Previous studies have identified neurons in the postsubiculum which discharge as a function of the animal's head direction in the horizontal plane, independent of its behavior and location in the environment. Anatomical studies have shown that the postsubiculum contains reciprocal connections with the anterior thalamic nuclei (ATN). In order to determine how the head direction (HD) cell signal is processed in the brain, single-unit recordings were monitored in the ATN of freely moving rats in order to characterize their behavioral and spatial correlates. Animals were trained to retrieve food pellets thrown randomly into a cylindrical apparatus containing a single orientation cue. Single unit recordings in the ATN showed that approximately 60% of the recorded cells discharged in relation to the animal's head direction in the horizontal plane. Observation of the animal and quantitative analyses showed that HD cell firing was not dependent on the animal's behavior, trunk position, linear speed, angular head velocity, or location in the environment. Most of these cells were localized to the anterior dorsal thalamic nucleus. Each HD cell contained only one head direction at which the cell discharged maximally and the firing rate decreased linearly away from this preferred direction. The preferred firing directions from all cells recorded were distributed over a 360 degrees range. Quantitative analysis showed that these cells contained similar discharge parameters (peak firing rate, directional firing range) to values reported previously for postsubicular HD cells (Taube et al., 1990a). Experiments involving rotation of the orientation cue showed that the preferred firing direction could be controlled by a salient visual cue. In contrast to postsubicular HD cells, passive rotation of a restrained animal showed that most ATN HD cells ceased discharging when the animal's head was oriented in the preferred direction. These findings demonstrate the presence of HD cells in the ATN and indicate the potential importance of this area for spatial navigation. The origin of the head direction signal is discussed and it is concluded that because of the presence of reciprocal connections between the postsubiculum and the ATN, further studies are required in order to determine the direction in which this head-directional information is flowing. Finally, ATN HD cells differ from postsubicular HD cells by appearing to require volitional motoric input.

Inhibition of long-term potentiation in the dentate gyrus of freely moving rats by the metabotropic glutamate receptor antagonist MCPG

Metabotropic glutamate receptors (mGluRs) are critically involved in the maintenance of long-term potentiation (LTP) (Reymann and Matthies, 1989; Behnisch et al., 1991; Izumi et al., 1991; Bashir et al., 1993). In order to assess further the physiological role of MGluRs in LTP, we injected freely moving rats with the recently available, competitive mGluR antagonist (R,S)-alpha-methyl-4-carboxyphenylglycine (MCPG) intraventricularly and recorded extracellularly the population spike (PS) as well as the field excitatory postsynaptic potential (fEPSP) of the granule cells of the dentate gyrus in response to stimulation of fibers of the perforant path. MCPG was administered in two concentrations (A = 20 mM/5 microliters; B = 200 mM/5 microliters) either 30 min prior to or 5 min after LTP induction. Sodium chloride infusion served as a control. Normal synaptic transmission was not altered by MCPG. However, the mGluR antagonist inhibited LTP in a concentration-dependent manner. Concentration A did not influence the potentiation shortly after the tetanus. In the PS, short-term potentiation (STP), which is decremental in its time course, occurred normally, but in contrast to controls the potentiation declined back to baseline values after 2-3 hr. This dose also reduced the posttetanic increase in the slope function of the fEPSP, and led to a time course of potentiation similar to that for the PS. Concentration B completely abolished the tetanus-induced potentiation. This block was similar to that obtained for the NMDA antagonist 2-amino-5-phosphonopentanoate (AP5). Both MCPG concentrations had no influence on the time course of preestablished LTP. These effects seem to be due to the action of the (+)-isomer of MCPG, since intracerebroventricular application of the (-)-isomer was without effect on the duration and magnitude of LTP. In addition, we were interested in the mGluR subtypes involved in the blocking mechanism of MCPG. 1S,3R-aminocyclopentane-1,3-dicarboxic acid (ACPD)-activated PPI hydrolysis in hippocampal slices was competitively inhibited by MCPG at a concentration of 1 mM or higher. In contrast, this concentration of MCPG did not affect the reduction of forskolin-stimulated cAMP formation by ACPD. These results corroborate recent findings that mGluRs are required for the induction of LTP in CA1 and CA3 in vitro (Bashir et al., 1993; Sergueeva et al., 1993) and in vivo (Riedel and Reymann, 1993). The process of STP is found to be independent of mGluR activation.(ABSTRACT TRUNCATED AT 400 WORDS)

Glycine antagonists block the induction of long-term potentiation in CA1 of rat hippocampal slices

The effects of the strychnine-insensitive glycine receptor antagonists, cycloleucine and 7-chlorokynurenic acid, on the induction of long-term potentiation (LTP) in CA1 of rat hippocampal slices were examined. A 5 min administration of cycloleucine (20–100 μM) or 7-chlorokynurenic acid (1–5 μM) during the delivery of high-frequency stimulation blocked the induction of LTP without affecting baseline synaptic transmission. Coapplication of 100 μM glycine with cycloleucine or 7-chlorokynurenic acid masked the inhibitory effect on the induction of LTP, supporting the hypothesis that these compounds act as glycine antagonists. These results indicate that glycine is a necessary factor for the induction of LTP in CA1 of the rat hippocampus.

Increased Ca-uptake of presynaptic terminals during long-term potentiation in hippocampal slices.

A combined electrophysiological and neurochemical study was performed on the CA1 area of hippocampal slices in an attempt to identify changes in presynaptic nerve terminal function in long-term potentiation (LTP). After controlled induction of LTP in CA1, the activated region was subjected to subcellular fractionation followed by 45Ca2+ uptake determinations. Synaptosomes prepared from slices in which LTP has been induced showed a faster risetime and a higher level of saturation for K+-induced Ca-uptake than those derived from unstimulated and stimulated control slices. These findings point to a participation of presynaptic terminals in long-term potentiation.