EPSP-spike Potentiation Research Articles

Differential Inhibition of E-S Potentiation and Long-term Potentiation by Cell-Derived and Arctic Amyloid Beta

Soluble oligomers of amyloid-beta peptide (Abeta) have been implicated in the onset of memory deficits in Alzheimer's disease, perhaps due to their reported ability to impair long-term potentiation (LTP) of synaptic strength. We previously showed the effect of Abeta on LTP depends on the strength of LTP induction. Furthermore, Abeta affects EPSP-Spike (E-S) potentiation more robustly than LTP, suggesting that E-S potentiation may be equally important to learning and memory in the context of Alzheimer's disease. Here we extend our findings to two additional forms of Abeta that form higher concentrations of soluble Abeta oligomers and show that they also affect E-S potentiation at induction strengths where there is no effect on LTP in hippocampal slices.

Hippocampal LTP modulation and glutamatergic receptors following vestibular loss.

Vestibular dysfunction strongly impairs hippocampus-dependent spatial memory performance and place cell function. However, the hippocampal encoding of vestibular information at the synaptic level, remains sparsely explored and controversial. We investigated changes in in vivo long-term potentiation (LTP) and NMDA glutamate receptor (NMDAr) density and distribution after bilateral vestibular lesions (BVL) in adult rats. At day 30 (D30) post-BVL, the LTP of the population spike recorded in the dentate gyrus (DG) was higher in BVL rats, for the entire 3h of LTP recording, while no difference was observed in the fEPSP slope. However, there was an increase in EPSP-spike (E-S) potentiation in lesioned rats. NMDArs were upregulated at D7 and D30 predominantly within the DG and CA1. At D30, we observed a higher NMDAr density in the left hippocampus. NMDArs were overexpressed on both neurons and non-neuronal cells, suggesting a decrease of the entorhinal glutamatergic inputs to the hippocampus following BVL. The EPSP-spike (E-S) potentiation increase was consistent with the dorsal hippocampus NMDAr upregulation. Such an increase could reflect a non-specific enhancement of synaptic efficacy, leading to a disruption of memory encoding, and therefore might underlie the memory deficits previously reported in rats and humans following vestibular loss.

Kv4 potassium channels modulate hippocampal EPSP-spike potentiation and spatial memory in rats

Kv4 channels regulate the backpropagation of action potentials (b-AP) and have been implicated in the modulation of long-term potentiation (LTP). Here we showed that blockade of Kv4 channels by the scorpion toxin AmmTX3 impaired reference memory in a radial maze task. In vivo, AmmTX3 intracerebroventricular (i.c.v.) infusion increased and stabilized the EPSP-spike (E-S) component of LTP in the dentate gyrus (DG), with no effect on basal transmission or short-term plasticity. This increase in E-S potentiation duration could result from the combination of an increase in excitability of DG granular cells with a reduction of GABAergic inhibition, leading to a strong reduction of input specificity. Radioactive in situ hybridization (ISH) was used to evaluate the amounts of Kv4.2 and Kv4.3 mRNA in brain structures at different stages of a spatial learning task in naive, pseudoconditioned, and conditioned rats. Significant differences in Kv4.2 and Kv4.3 mRNA levels were observed between conditioned and pseudoconditioned rats. Kv4.2 and Kv4.3 mRNA levels were transiently up-regulated in the striatum, nucleus accumbens, retrosplenial, and cingulate cortices during early stages of learning, suggesting an involvement in the switch from egocentric to allocentric strategies. Spatial learning performance was positively correlated with the levels of Kv4.2 and Kv4.3 mRNAs in several of these brain structures. Altogether our findings suggest that Kv4 channels could increase the signal-to-noise ratio during information acquisition, thereby allowing a better encoding of the memory trace.

Homeostasis of intrinsic excitability: making the point

Homeostasis of intrinsic excitability: making the point

Impaired in vivo synaptic plasticity in dentate gyrus and spatial memory in juvenile rats induced by prenatal morphine exposure

Prenatal morphine exposure induces neurobiological changes, including deficits in learning and memory, in juvenile rat offspring. However the effects of this exposure on hippocampal plasticity, which is critical for learning and memory processes, are not well understood. The present study investigates the alterations of spatial memory and in vivo hippocampal synaptic plasticity in juvenile rats prenatally exposed to morphine. On gestation days 11-18, pregnant rats were randomly chosen to be injected twice daily with morphine or saline. Each juvenile offspring (postnatal day 22-31) performed one two-trial Y-maze task to evaluate spatial memory. Afterwards, the in vivo field excitatory postsynaptic potential (fEPSP) and population spike (PS) were recorded in the perforant path dentate gyrus (DG) pathway in the hippocampus. Prenatal morphine exposure reduced depotentiation (DP), but not long-term potentiation (LTP), of the EPSP slope. However, both LTP and DP of the EPSP slope were depressed in prenatal morphine-exposed juvenile offspring. The morphine group also showed poorer performance for the Y-maze task than the control group. Depressed PS LTP, but not EPSP LTP, in the morphine group suggested that prenatal morphine exposure changed GABAergic inhibition, which mediates EPSP-spike potentiation. Then a loss of GABA-containing neurons in the DG area of the morphine group was observed using immunohistochemistry. Taken together, our results suggest that prenatal morphine exposure impairs the juvenile offspring's dentate synaptic plasticity and spatial memory, and that decreased GABAergic inhibition may play a role in these effects. These findings might contribute to an explanation for the cognitive deficits in children whose mothers abuse opiates during pregnancy.

Differential cholinergic modulation of synaptic encoding and gain control mechanisms in rat hippocampus

Recent studies have highlighted a variety of cognitive effects caused by cholinolytic drug injections into different cortical structures. These findings were largely interpreted as evidence for location-specific cholinergic modulation of synaptic encoding mechanisms. Here, using evoked field responses in anaesthetized rat dorsal hippocampus we show that in addition to reinforcement of synaptic connections (long-term potentiation, LTP), endogenous acetylcholine also regulates firing gain of CA1 pyramidal neurons (EPSP-spike potentiation). Gain augmentation upon increase in cholinergic drive involves evoked synchronous firing at both apical and basal afferent projections, unlike enhancement of activity-induced LTP constrained to the basal afferent system. These data indicate that acetylcholine can act as an effective input and gain controller in the hippocampus. Modulation of synaptic plasticity would determine the relative dominance of afferent inputs while the facilitation of synchronous firing is likely to promote a more generalized spread of excitation and long range communication within the limbic cortex.

MDMA Induces EPSP–Spike Potentiation in Rat Ventral Hippocampus In Vitro Via Serotonin and Noradrenaline Release and Coactivation of 5-HT4 and β1 Receptors

It is well documented that N-methyl-3,4-methylenedioxyamphetamine (MDMA, ecstasy) releases brain serotonin (5-HT; 5-hydroxytryptamine), noradrenaline (NE; norepinephrine), and dopamine, but the consequent effect on brain functioning remains elusive. In this study, we characterized the effects of MDMA on electrically evoked responses in the ventral CA1 region of a rat hippocampal slice preparation. Superfusion with MDMA (10 microM, 30 min) increased the population spike amplitude (PSA) by 48.9+/-31.2% and decreased population spike latency (PSL) by 103+/-139 mus (both: mean+/-SD, n=123; p<0.0001, Wilcoxon test), without affecting field excitatory postsynaptic potential (fEPSP). This effect persisted for at least 1 h after MDMA washout; we have called this EPSP-spike potentiation (ESP) by MDMA, ESP MDMA. Antagonism of GABAergic transmission did not prevent ESP MDMA, suggesting that an increase in excitability of pyramidal cells underlies this MDMA action. Block of serotonin transporter (SERT) with citalopram or 5-HT depletion with (+/-)-p-chlorophenylalanine pretreatment partially inhibited the ESP MDMA. Block of both SERT and NE transporter prevented ESP MDMA, indicating its dependence on release of both 5-HT and NE. ESP MDMA is produced by simultaneous activation of 5-HT4 and beta1 receptors, with a predominant role of 5-HT4 receptors. Block of both 5-HT4 and beta1 receptors revealed an inhibitory component of the MDMA action mediated by 5-HT1A receptor. The concentration range of MDMA which produced ESP MDMA (1-30 microM) corresponds to that commonly reached in human plasma following the ingestion of psychoactive MDMA doses, suggesting that release of both 5-HT and NE, and consequent ESP MDMA may underlie some of the psychoactive effects of MDMA in humans.

5‐HT4 receptor activation induces long‐lasting EPSP‐spike potentiation in CA1 pyramidal neurons

Recent studies implicated involvement of the 5-hydroxytryptamine4 (5-HT4) receptor in cognitive and emotional processes. The highest 5-HT4 receptor densities in the brain are found in the limbic system including the hippocampus. Here we used the selective 5-HT4 receptor full agonist, N-pentyl-N'-aminoguanidine carbazimidamide (SDZ-216454) to characterize effects of 5-HT4 receptor activation in whole-cell and field recordings in the area CA1 in hippocampal slices prepared from 3 to 4- and 6 to 9-week-old rats, respectively. Extracellular recordings showed that transient 5-HT4 receptor activation by 10-20 min application of SDZ-216454 induces field excitatory postsynaptic potential (fEPSP)-population spike potentiation (ESP(5-HT4)), which persisted for as long as we held the recordings (> 2 h). ESP(5-HT4) displayed characteristics different from EPSP-spike potentiation that accompanies long-term potentiation; it developed without an associated increase in synaptic transmission, was independent on afferent input, activity of postsynaptic neurons and N-methyl-d-aspartate receptor activation; and was expressed in the presence of GABA receptor antagonists. ESP(5-HT4) was also induced by transient application of the natural neurotransmitter, 5-HT. The increase in the evoked population spike (PS) induced by SDZ-216454 was not prevented by blockers of hyperpolarization-activated cation current (Ih), Cs+ and ZD-7288, but was mimicked and occluded by 150 microm Ba2+. Whole-cell voltage-clamp recordings from pyramidal neurons demonstrated that SDZ-216454 application increases membrane resistance with a concomitant decrease in a Ba2+-sensitive inwardly rectifying K+ current and the Ba2+-insensitive K+ current underlying slow afterhyperpolarization (I(sAHP)). We conclude that 5-HT4 receptor activation may cause a long-lasting excitability increase in CA1 pyramidal neurons by inhibition of a Ba2+-sensitive inwardly rectifying K+ current.

The birth (and adolescence) of LTP

The birth (and adolescence) of LTP

Timing and balance of inhibition enhance the effect of long-term potentiation on cell firing.

The role of a neuron in neural processing is ultimately determined by whether or not it fires an action potential in a given context. Studies on synaptic plasticity have focused primarily on changes in EPSPs, and not on whether plasticity translates into changes in firing. However, this issue has been addressed by examining EPSP-spike (E-S) potentiation, which enhances the ability of an EPSP of a fixed slope to elicit spikes after long-term potentiation (LTP). Although LTP is thought to underlie learning and memory, E-S potentiation could play an equally important role by potentiating the neuronal input-output function. Here, we used a combined experimental and theoretical approach to examine both the mechanisms underlying E-S potentiation as well as the role of inhibition in shaping the input-output function of neurons. Whereas previous studies examined tetanus-LTP, in which inhibitory synapses may have undergone plasticity, here we examined pairing-induced associative LTP. We determined that although intact inhibition was necessary for pairing-induced E-S potentiation, inhibitory plasticity was not. We further established using computer simulations that a primary mechanism of E-S potentiation was a change in the relative recruitment and latency of inhibitory neurons. Although these studies do not exclude the presence of additional mechanisms of E-S potentiation that may be engaged depending on the induction protocol, they do establish that under intact pharmacology, LTP of the Schaffer collateral to CA1 pyramidal neuron synapses will produce E-S potentiation as a result of changes in the balance and timing of excitation and inhibition.

Intracellular correlate of EPSP-spike potentiation in CA1 pyramidal neurons is controlled by GABAergic modulation.

The hippocampus has been used extensively as a model to study plastic changes in the brain's neural circuitry. Immediately after high-frequency stimulation to hippocampal Schaffer collateral axons, a dramatic change occurs in the relationship between the presynaptic CA3 and the postsynaptic CA1 pyramidal neurons. For a fixed excitatory postsynaptic potential (EPSP), there arises an increased likelihood of action potential generation in the CA1 pyramidal neuron. This phenomenon is called EPSP-spike (E-S) potentiation. We explored E-S potentiation, using patch-clamp techniques in the hippocampal slice preparation. A specific protocol was developed to measure the action potential probability for a given synaptic strength, which allowed us to quantify the amount of E-S potentiation for a single neuron. E-S potentiation was greatest when gamma-aminobutyric acid (GABA)ergic inhibition was intact, suggesting that modulation of inhibition is a major aspect of E-S potentiation. Expression of E-S potentiation also correlated with a reduced action-potential threshold, which was greatest when GABAergic inhibition was intact. Conditioning stimuli produced a smaller threshold reduction when inhibition was blocked, but some reduction also occurred in the absence of a conditioning stimulus. Together, these results suggest that E-S potentiation is caused primarily through a reduction of GABAergic inhibition, leading to larger EPSPs and reduced action potential threshold. Our findings do not rule out, however, the possibility that modulation of voltage-gated conductances also contributes to E-S potentiation.

Differential Effects of Short- and Long-Term Potentiation on Cell Firing in the CA1 Region of the Hippocampus

Long-term potentiation (LTP) in the hippocampus enhances the ability of a stimulus to produce cell firing, not only by increasing the strength of the EPSPs, but also by increasing the efficiency of the input/output (I/O) function of pyramidal neurons. This means that EPSPs of a given size more easily elicit spikes after LTP, a process known as EPSP-spike (E-S) potentiation. In contrast to LTP, it is not known whether the synaptic strengthening produced by paired-pulse facilitation (PPF) also results in changes in the I/O function. We have addressed this question by examining E-S curves from rat hippocampal area CA1 in response to both PPF and LTP. We describe a novel form of I/O modulation in which PPF produces E-S depression; that is, the E-S curve is shifted to the right, indicating a decreased ability of EPSPs to elicit action potentials. Consistent with the notion that E-S potentiation observed with LTP is caused by long-term increases in the excitatory-inhibitory ratio, we show that PPF-induced E-S depression relies on short-term decreases in this ratio. These results indicate that different forms of synaptic plasticity that produce the same degree of EPSP potentiation can result in dramatically different effects on cell firing, because of the dynamic changes in the excitatory-inhibitory balance within local circuits.

Neuronal hyperexcitability induced by repeated brief episodes of hypoxia in rat hippocampal slices: involvement of ionotropic glutamate receptors and L-type Ca 2+ channels

Repeated exposures of rat hippocampal slices to short episodes of hypoxia induce a sustained decrease in the threshold of the development of stimulus-evoked epileptiform discharges in CA1 pyramidal neurons. We have previously demonstrated that the K + o-induced hyperexcitability required functional L-type voltage-dependent Ca 2+ channels and NMDA-receptors, but was independent of AMPA/kainate-receptor activation. As hypoxia/ischaemia can lead to increased K + o, the epileptiform activity observed after exposure to these challenges could also result from high K + o. The purpose of this study was: (i) to determine whether ionotropic glutamate receptors and L-type Ca 2+ channels are involved in the development of epileptiform activity induced by repeated exposures of hippocampal slices to hypoxia; and (ii) to compare the properties of hypoxia- and high K + o-induced hyperexcitability. Population spike of presynaptic fibres with field excitatory postsynaptic potential from the stratum radiatum, and population spike of CA1 pyramidal neurons from the stratum pyramidale, were recorded simultaneously in the CA1 area of rat hippocampal slices in response to electrical stimulation of the Schaffer collateral/commissural fibres. Repeated, brief hypoxic episodes induced a sustained decrease in the threshold for development of evoked epileptiform discharges that was associated with long-term potentiation of the CA3-CA1 synapses, but without EPSP-spike potentiation (i.e. in contrast to high K + o-induced hyperexcitability). The selective antagonist of NMDA receptors, D-APV (25 μM), and the selective blocker of L-type Ca 2+ channels, nifedipine (10 μM) depressed the development of hypoxia-induced hyperexcitability. However, in contrast to high K + o-induced hyperexcitability, hypoxia-induced hyperexcitability was also blocked by the AMPA/kainite-receptor antagonist, CNQX (5 μM). The present findings confirm that repeated, brief episodes of hypoxia, like exposure to high extracellular K +, can induce a pro-epileptic state in the CA1 neuronal network, but that the mechanisms leading to hyperexcitability are different for the two stimuli.

The supramammillary nucleus contributes to associative EPSP-spike potentiation in the rat dentate gyrus in vivo.

The supramammillary nucleus (SUM) of the hypothalamus sends neural projections to the hippocampus and is supposed to be involved in learning and memory. To test the possibility that SUM afferents modulate hippocampal functions, we investigated the effect of electrical stimulation of the SUM on the induction of long-term potentiation (LTP) at medial perforant path (PP)--granule cell synapses in the dentate gyrus (DG) of anaesthetized rats. High-frequency stimulation of the SUM (100 pulses at 100 Hz) alone did not change PP--DG field potentials. However, when the SUM stimulation was applied simultaneously with weak tetanic stimulation of the PP (20 pulses at 20 Hz) which alone did not induce any potentiation, it produced a long-lasting potentiation of the population spike, without an accompanying increase in the population excitatory postsynaptic potential (EPSP). The EPSP-spike (E-S) potentiation induced by pairing SUM and PP stimulation was abolished by lesions of the fimbria--fornix, a major pathway of SUM afferents. SUM stimulation applied 1 s before or after PP stimulation failed to produce E-S potentiation, and SUM stimulation augmented PP--DG field potentials during tetanic stimulation. Furthermore, the E-S potentiation was abolished by blocking GABAergic neurotransmission with picrotoxin. These results suggest that coactivation of SUM and PP inputs produces a long-lasting increase of granule cell excitability by modulating GABAergic inhibition. SUM afferents may contribute to associative memory processing by modulating hippocampal excitability.

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.

Epileptiform activity and EPSP-spike potentiation induced in rat hippocampal CA1 slices by repeated high-K +: involvement of ionotropic glutamate receptors and Ca 2+/calmodulin-dependent protein kinase II

We have previously demonstrated that repeated brief increases in extracellular K + (K + o) induce a hyperexcitability in CA1 pyramidal cells that persists for a long time after the final application of K + [Neurosci. Lett. 223 (1997) 177; Epilepsy Research (2000) 75]. This epileptiform activity, which was associated with a lasting excitatory postsynaptic potential (EPSP)-spike potentiation, presented some of the characteristic features of traditional in vivo kindling. We have also found that Ca 2+ influx through L-type voltage-sensitive Ca 2+ channels is essential for the development of both in vitro kindling and EPSP-spike potentiation. The aims of this study were to investigate the involvement of ionotropic glutamate receptors, especially those of the NMDA subtype, and the requirement for Ca 2+/calmodulin-dependent protein kinase II (CaMKII) in these phenomena. Field EPSPs with presynaptic fibre volleys from the stratum radiatum, and population spikes from the stratum pyramidale, were recorded in the CA1 area of rat hippocampal slices in response to electrical stimulation of the Schaffer collateral/commissural fibres. Repeated (three episodes) brief (30 s) increases in extracellular K + induced a sustained decrease in the threshold for development of evoked epileptiform discharges (i.e. an in vitro kindling-like state) and a lasting potentiation of the EPSP-spike transfer in CA1 pyramidal neurons (EPSP-spike potentiation). The selective antagonist of NMDA receptors, APV (50 μM), blocked the EPSP-spike potentiation, depressed the induction phase of the in vitro kindling-like state, and blocked the maintenance phase of this state. In contrast to APV, the blockade of AMPA/kainate receptors by CNQX (10 μM) had no effect. Like APV, KN62 (3 μM), a selective membrane permeable inhibitor of CaMKII, blocked the EPSP-spike potentiation and the maintenance phase of the in vitro kindling-like state. Our previous and present results therefore demonstrate that Ca 2+ influxes through L-type voltage-dependent—and NMDA receptor-dependent—Ca 2+ channels contribute differentially to the development of an in vitro kindling-like state, and both induce EPSP-spike potentiation in CA1 hippocampal pyramidal cells in response to repeated brief increases in K + o. It is suggested that these effects of intracellular Ca 2+ on the maintenance phase of the in vitro kindling-like state and EPSP-spike potentiation are mediated by CaMKII-dependent mechanisms.

Full length article

The muscarinic acetylcholine receptor antagonist scopolamine, but not the beta-adrenoceptor antagonist propranolol or atenolol, suppressed tetanus-induced long-term potentiation (LTP) of population spikes in the rat hippocampal CA1 region. When scopolamine was coapplied with propranolol or atenolol, a synergistic effect in preventing LTP generation was observed. On the other hand, the coapplication of scopolamine and atenolol failed to affect tetanus-induced LTP of field EPSP. These findings suggest that cooperative mechanisms via muscarinic and beta-adrenergic receptor activation might contribute to LTP induction in terms of the EPSP-spike potentiation, i.e., an increase in the excitability of hippocampal CA1 pyramidal cells after tetanic stimulation, but are independent of the tetanus-evoked potentiation of a synaptic component.

Metabotropic glutamate receptor dependent EPSP and EPSP-spike potentiation in area CA1 of the submerged rat hippocampal slice.

1. We reexamined the important areas of conflict in (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD]-induced potentiation of the field excitatory postsynaptic potential (EPSP) and, for the first time, investigated the role of mGluRs in EPSP-spike (E-S) coupling. 2. (1S,3R)-ACPD (10 microM) bath applied for 20 min consistently induced a long-lasting potentiation of the dendritic EPSP in area CA1 of submerged rat hippocampal slices, which was considerably faster in onset than described previously. 3. This effect was not associated with any change in presynaptic fiber volley but was dependent on both an intact CA3 connection, because removal of area CA3 blocked (1S,3R)-ACPD-induced potentiation, and also on functional N-methyl-D-aspartate (NMDA) receptors, because (1S,3R)-ACPD-induced potentiation was blocked by inclusion of the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (AP5; 50 microM). 4. (1S,3R)-ACPD induced a long-lasting potentiation of the population spike (PS) amplitude that was consistently larger than that of the EPSP measured in the cell body area. This EPSP-PS (E-S) potentiation was blocked by inclusion of the gamma-aminobuturic acid-A (GABAA) receptor antagonist, picrotoxin (50 microM). 5. E-S potentiation induced by high-frequency stimulation (HFS), which was of the same magnitude as that induced by (1S,3R)-ACPD, was blocked by the mGluR-selective antagonist (+)-alpha-methyl-4-carboxyphenylglycine (+MCPG; 250 microM). +MCPG also blocked HFS-induced long-term potentiation (LTP) of the EPSP measured in the cell body. 6. These results suggest that (1S,3R)-ACPD-induced potentiation is NMDA receptor dependent, contrary to some previous findings, and provide further evidence that both synaptic and E-S potentiation induced by (1S,3R)-ACPD share common mechanisms of expression with HFS-induced LTP. The data emphasize the important role of mGluRs in induction of EPSP LTP and E-S potentiation.

A role for synaptic and network plasticity in controlling epileptiform activity in CA1 in the kainic acid-lesioned rat hippocampus in vitro.

1. Stimulation of the surviving afferents in the stratum radiatum of the CA1 area in kainic acid-lesioned hippocampal slices produced graded epileptiform activity, part of which (> 20%) involved the activation of N-methyl-D-aspartate (NMDA) receptors. There was also a failure of synaptic inhibition in this region. In this preparation, we have tested the effects of low-frequency stimulation (LFS; 1 Hz for 15 min) on synaptic responses and epileptiform activity. 2. LFS resulted in long-term depression (LTD) of excitatory synaptic potentials (EPSPs), long-term decrease of population spike amplitudes (PSAs) and EPSP-spike (E-S) potentiation. Evoked epileptiform activity was reduced but neurons had a higher probability of discharge. LTD could be reversed by subsequent tetanic stimulation whereas E-S dissociation remained unchanged. Synaptic and network responses could be saturated towards either potentiation or depression. However, E-S potentiation was maximal following the first conditioning stimulus. 3. NMDA receptor-mediated responses were pharmacologically isolated. LFS resulted in LTD of synaptic responses, long-term decrease of PSAs and E-S depression. These depressions could not be reversed by subsequent tetanic stimulation. alpha-Amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) and NMDA receptor-mediated responses were then measured in isolation before and following conditioning stimuli. LFS was shown to simultaneously produce LTD of AMPA and NMDA receptor-mediated responses. E-S potentiation of the AMPA component and E-S depression of the NMDA component occurred coincidentally. 4. LTD of AMPA and NMDA receptor-mediated responses were shown to be NMDA dependent. In contrast, E-S potentiation and depression occurred even when NMDA receptors were pharmacologically blocked. 5. These findings indicate that synaptic responses could be modified bidirectionally in the CA1 area of kainic acid-lesioned rat hippocampus in an NMDA receptor-dependent manner. However, E-S dissociations were independent of the activation of NMDA receptors, hinting at mechanisms different from those of synaptic LTD. We suggest that changes in E-S coupling were caused by a modification of the firing threshold of the CA1 pyramidal neurons. Furthermore, the firing mechanisms controlling NMDA and AMPA receptor-mediated network activity appeared to be different. The possible use of LFS applied to the hippocampus as a clinical intervention to suppress epileptiform activity is discussed.

Epsp-spike potentiation during primed burst-induced long-term potentiation in the ca1 region of rat hippocampal slices

Long-term potentiation induced by high-frequency stimulation in the CA1 region of the hippocampus exhibits EPSP-spike potentiation. This consists of an increase in population spike amplitude exceeding that predicted by EPSP potentiation alone. This phenomenon is apparently due to an increase in pyramidal cell excitability. Patterns of afferent stimuli which activate pyramidal cells to reproduce the theta rhythm observed in the hippocampus under physiological conditions, have been shown to induce LTP-like enhancement of synaptic responses in vitro. The aim of this study was to investigate the presence of EPSP-spike potentiation and/or changes in pyramidal cell excitability during the long-term potentiation induced in the CA1 region of rat hippocampal slices by theta-like patterns of stimuli: the primed burst and the patterned stimulation. Using extracellular recording, a significant leftward shift in the EPSP-spike relationship was found 30 min after primed burst or patterned stimulation. The magnitude of EPSP-spike potentiation induced by patterned stimulation was similar to that produced by high-frequency stimulation. Both were significantly greater than that induced by a primed burst, indicating that only a subset of pyramidal cells were potentiated by this kind of afferent activation. Modifications in synaptic efficacy and cell excitability brought about by a primed burst were investigated in 25 intracellularly recorded pyramidal cells. Consistent with extracellular results, it was found that only 11 out of 25 neurons receiving a primed burst were potentiated. In these cells the increase in probability of firing action potentials elicited by synaptic activation with test shocks was accompanied by enhanced cell excitability, but not by an increase in EPSP slope. High-frequency stimulation delivered 40 min after a primed burst invariably increased the EPSP slope, the probability of firing upon synaptic stimulation, and the excitability of cells. The presence of EPSP-spike potentiation and of increased excitability of potentiated cells during the primed burst-induced long-term potentiation strengthen the suggestion that theta pattern-induced synaptic potentiation can be considered similar to high-frequency stimulation and long-term potentiation and supports the notion that the EPSP-spike potentiation is a constitutive characteristic of long-term potentiation.