Relations Between Long-term Synaptic Modifications and Paired-pulse Interactions in the Rat Neocortex

The phenomenon of paired-pulse facilitation (PPF) was exploited to investigate the role of presynaptic mechanisms in the induction and maintenance of long-term synaptic plasticity in the neocortex. Long-term potentiation (LTP) and depression (LTD) were induced without afferent activation by applying tetani of intracellular pulses. Our results show that synaptic modifications closely resembling LTP and LTD can be induced by postsynaptic activation alone. The polarity of these synaptic modifications depends on initial properties of the input, as indicated by a correlation between initial PPF ratio and post-tetanic amplitude changes: inputs exhibiting strong PPF, which might be associated with low release probability tend to be potentiated, while inputs with small PPF are more likely to show depression. Maintenance of both LTP and LTD involve presynaptic mechanisms, as indicated by changes in PPF ratios and in failure rate after LTP or LTD induction. Presynaptic mechanisms could include changes in release probability and/or in the number of active release sites. Because induction was postsynaptic, this supports the notion of a retrograde signal. The relative contribution of pre- and postsynaptic mechanisms in the maintenance of long-term synaptic modifications depends on the initial state of the synaptic input and on LTP magnitude. PPF changes were especially pronounced in inputs which had initially high PPF and underwent strong potentiation. Since LTP and LTD are associated with changes of PPF ratios these synaptic modifications do not only alter the gain but also the temporal properties of synaptic transmission. Because of the LTP associated reduction of PPF, potentiated inputs profit less from temporal summation, favouring transmission of synchronized, low frequency activity.     

Physiological significance of long-term potentiation.

Long-term potentiation (LTP) is a form of synaptic plasticity that follows repetitive, high frequency stimulation of excitatory presynaptic fibers. It produces a long-lasting enhancement of synaptic strength that is usually revealed as an increased size of excitatory postsynaptic potentials. It is most prominent in the hippocampus, although it may be evoked in other brain regions. Use-dependent modifications in synaptic function are probably the basis of learning and memory, thus the study of LTP may represent a useful model for investigating the physiological mechanisms underlying the process of information storage.     

Long-lasting modulation of the induction of LTD and LTP in rat hippocampal CA1 by behavioural stress and environmental enrichment

Behavioural experience (e.g. chronic stress, environmental enrichment) can have long-lasting effects on cognitive functions. Because activity-dependent persistent changes in synaptic strength are believed to mediate memory processes in brain areas such as hippocampus, we tested whether behaviour has also long-lasting effects on synaptic plasticity by examining the induction of long-term potentiation (LTP) and long-term depression (LTD) in slices of hippocampal CA1 obtained from rats either 7-9 months after social defeat (behavioural stress) or 3-5 weeks after 5-week exposure to environmental enrichment. Compared with age-matched controls, defeated rats showed markedly reduced LTP. LTP was even completely impaired but LTD was enhanced in defeated and, subsequently, individually housed (during the 7-9-month period after defeat) rats. However, increasing stimulus intensity during 100-Hz stimulation resulted in significant LTP. This suggests that the threshold for LTP induction is still raised and that for LTD lowered several months after a short stressful experience. Both LTD and LTP were enhanced in environmentally enriched rats, 3-5 weeks after enrichment, as compared with age-matched controls. Because enrichment reduced paired-pulse facilitation, an increase in presynaptic release, facilitating both LTD and LTP induction, might contribute to enhanced synaptic changes. Consistently, enrichment reduced the number of 100-Hz stimuli required for inducing LTP. But enrichment may also actually enhance the range of synaptic modification. Repeated LTP and LTD induction produced larger synaptic changes in enriched than in control rats. These data reveal that exposure to very different behavioural experiences can produce long-lasting effects on the susceptibility to synaptic plasticity, involving pre- and postsynaptic processes.     

Induction mechanisms and modulation of bidirectional burst stimulation-induced synaptic plasticity in the hippocampus

Spike bursting is an important physiological mode of the hippocampus. Whereas the rules of spike timing-dependent synaptic plasticity are well defined for pairs of single action potentials (APs) and excitatory postsynaptic potentials (EPSPs), long-term modification of synaptic responses is much less understood for more complex pre- and postsynaptic spike patterns. We induced a burst stimulation (BS)-associated form of synaptic plasticity in rat CA1 hippocampal slices by repeatedly pairing three EPSPs with a burst of APs induced by postsynaptic current injection. In distinct groups of cells, this induction paradigm resulted in long-term potentiation (LTP), long-term depression (LTD) or no change in synaptic strength. LTP was N -methyl- d -aspartate receptor-dependent, whereas LTD could be blocked by a metabotropic glutamate receptor antagonist or inhibition of Ca²⁺ influx through voltage-activated Ca²⁺ channels. LTP was predicted by a more depolarized membrane potential and a higher initial AP frequency. LTD was facilitated by a larger time interval between the last EPSP and its preceding AP. We conclude from these findings that associative BS induces a bidirectional form of long-term synaptic plasticity that cannot be fully explained by spike timing rules. Postsynaptic membrane potential and Ca²⁺ influx further influence the sign and magnitude of synaptic modification. LTP and LTD have distinct mechanisms and can be selectively modulated. This supports the concept of two independent coincidence detectors for LTP and LTD, and extends the physiological options to modulate synaptic plasticity and maintain a putative balance between potentiation and depression in synaptic networks.     

Diabetes mellitus concomitantly facilitates the induction of long-term depression and inhibits that of long-term potentiation in hippocampus

Memory impairments, which occur regularly across species as a result of ageing, disease (such as diabetes mellitus) and psychological insults, constitute a useful area for investigating the neurobiological basis of learning and memory. Previous studies in rats found that induction of diabetes (with streptozotocin, STZ) impairs long‐term potentiation (LTP) but enhances long‐term depression (LTD) induced by high‐ (HFS) and low‐frequency stimulations (LFS), respectively. Using a pairing protocol under whole‐cell recording conditions to induce synaptic plasticity at Schaffer collateral synapses in hippocampal CA1 slices, we show that LTD and LTP have similar magnitudes in diabetic and age‐matched control rats. But, in diabetic animals, LTD is induced at more polarized and LTP more depolarized membrane potentials (V_ms) compared with controls: diabetes produces a 10 mV leftward shift in the threshold for LTD induction and 10 mV rightward shift in the LTD–LTP crossover point of the voltage–response curve for synaptic plasticity. Prior repeated short‐term potentiations or LTP are known to similarly, though reversibly, lower the threshold for LTD induction and raise that for LTP induction. Thus, diabetes‐ and activity‐dependent modulation of synaptic plasticity (referred to as metaplasticity) display similar phenomenologies. In addition, compared with naïve synapses, prior induction of LTP produces a 10 mV leftward shift in V_ms for inducing subsequent LTD in control but not in diabetic rats. This could indicate that diabetes acts on synaptic plasticity through mechanisms involved in metaplasticity. Persistent facilitation of LTD and inhibition of LTP may contribute to learning and memory impairments associated with diabetes mellitus.     

Distinct mechanisms of bidirectional activity-dependent synaptic plasticity in superficial and deep layers of rat entorhinal cortex

The entorhinal cortex plays a key role in processing memory information in the brain; superficial layers relay information to, and deep layers receive information from, the hippocampus. The cellular mechanisms of memory are thought to include a number that produce long-term potentiation (LTP) and depression (LTD) of synaptic strength. Our work presents evidence that LTP and LTD occur simultaneously at memory-relevant synapses. We report here that low frequency stimulation generates NMDA receptor-dependent LTD in Wistar rat superficial (layers II and III), and LTP in the deep entorhinal cortex layers (layers V and VI). LTP in deep layers is masked by simultaneously occurring voltage-gated calcium channel-dependent LTD. Our data support a novel mechanism for the sliding-threshold (BCM) model of synaptic plasticity: The sliding thresholds for induction of LTP and LTD in entorhinal cortex deep layers will be driven by the relative activation state of NMDA receptors and voltage-gated calcium channels. The co-expression of LTD and LTP at presynaptic sites in the entorhinal cortex deep layers reveals an intriguing mechanism for differential processing of synaptic information, which may underlie the vast dynamic capacity for information storage by this cortical structure.     

Overexpression of calbindin D(28k) in dentate gyrus granule cells alters mossy fiber presynaptic function and impairs hippocampal-dependent memory

Calcium is a key signaling ion for induction of synaptic plasticity processes that are believed to influence cognition. Mechanisms regulating activity-induced increases in neuronal calcium and related synaptic modifications are not fully understood. Moreover, involvement of specific synapses in discrete aspects of spatial learning remains to be elucidated. We used herpes simplex amplicons to overexpress calbindin D(28k) (CaBP) selectively in dentate gyrus (DG) granule cells. We then examined the effects on hippocampal network activity by recording evoked synaptic responses in vivo and in vitro and analyzing hippocampal-dependent behavior. Relative to Lac-Z- and sham-infected controls, CaBP overexpression increased mossy fiber (MF-CA3) excitatory postsynaptic potentials and reduced paired-pulse facilitation (PPF), suggesting an increase in presynaptic strength. Additionally, CaBP overexpression reduced long-term potentiation (LTP), caused a frequency-dependent inhibition of post-tetanic potentiation (PTP), and impaired spatial navigation. Thus, increasing CaBP levels selectively in the DG disrupts MF-CA3 presynaptic function and impairs spatial cognition. The results demonstrate the power of gene delivery in the study of the neural substrates of learning and memory and suggest that mossy fiber synaptic plasticity is critical for long-term spatial memory.     

Synaptic plasticity in the absence of backpropagating spikes of layer II inputs to layer V pyramidal cells in rat visual cortex

Use-dependent changes of synaptic transmission are thought to depend on the evaluation of temporal correlations between pre- and postsynaptic excitatory activity. Previous studies have demonstrated long-term potentiation (LTP) in layer V pyramidal cells after coincident pairing of presynaptic excitatory input with postsynaptic depolarizations, evoking backpropagating action potentials (BAPs). Here we paired excitatory layer II input with somatic hyperpolarization, which blocked BAPs in layer V pyramidal cells of rat visual cortex and induced reliable long-term depression (LTD). Upon cholinergic receptor activation, this BAP-independent protocol also induced LTP, which was not dependent on N-methyl-d-aspartate receptor activation, but blocked by metabotropic glutamate receptor (mGluR) antagonists.     

Synaptic Plasticity in an In Vitro Slice Preparation of the Rat Nucleus Accumbens

Extra- and intracellular recordings in slices were used to examine what types of synaptic plasticity can be found in the core of the nucleus accumbens, and how these forms of plasticity may be modulated by dopamine. Stimulus electrodes were placed at the rostral border of the nucleus accumbens in order to excite primarily infralimbic and prelimbic afferents, as was confirmed by injections of the retrograde tracer fluoro-gold. In extracellular recordings, tetanization induced long-term potentiation (LTP) of the population spike in 20 out of 53 slices. The presynaptic compound action potential did not change following LTP induction. For the intracellularly recorded excitatory postsynaptic potential, three types of synaptic plasticity were noted: long-term potentiation (16 out of 54 cells), decremental potentiation (eight cells) and long-term depression (LTD; six cells). No correlation was found between the occurrence of potentiation or depression and various parameters of the tetanic depolarization (e.g. peak voltage, integral under the curve). The N -methyl- d -aspartate receptor antagonist d (–)-2-amino-5-phosphonopentanoic acid (50 μM; d -AP5) reduced, but did not completely prevent, the induction of LTP. The incidence of LTD was not markedly affected by d -AP5. No difference in LTP was found when comparing slices bathed in dopamine (10 μM) and controls. Likewise, slices treated with a mixture of the D1 receptor antagonist Sch 23390 (1 μM) and the D2 antagonist S (–)-sulpiride (1 μM) generated a similar amount of LTP as controls. In conclusion, both LTP and LTD can be induced in a key structure of the limbic-innervated basal ganglia. LTP in the nucleus accumbens strongly depends on N -methyl- d -aspartate receptor activity, but is not significantly affected by dopamine.     

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.     

Calcium Channel-Dependent Induction of Long-Term Synaptic Plasticity at Excitatory Golgi Cell Synapses of Cerebellum

Golgi cells, together with granule cells and mossy fibers, form a neuronal microcircuit regulating information transfer at the cerebellum input stage. Despite theoretical predictions, little was known about long-term synaptic plasticity at Golgi cell synapses. Here, we have used whole-cell patch-clamp recordings and calcium imaging to investigate long-term synaptic plasticity at excitatory synapses impinging on Golgi cells. In acute mouse cerebellar slices, mossy fiber theta-burst stimulation (TBS) could induce either long-term potentiation (LTP) or long-term depression (LTD) at mossy fiber-Golgi cell and granule cell-Golgi cell synapses. This synaptic plasticity showed a peculiar voltage dependence, with LTD or LTP being favored when TBS induction occurred at depolarized or hyperpolarized potentials, respectively. LTP required, in addition to NMDA channels, activation of T-type Ca²⁺ channels, while LTD required uniquely activation of L-type Ca²⁺ channels. Notably, the voltage dependence of plasticity at the mossy fiber-Golgi cell synapses was inverted with respect to pure NMDA receptor-dependent plasticity at the neighboring mossy fiber-granule cell synapse, implying that the mossy fiber presynaptic terminal can activate different induction mechanisms depending on the target cell. In aggregate, this result shows that Golgi cells show cell-specific forms of long-term plasticity at their excitatory synapses, that could play a crucial role in sculpting the response patterns of the cerebellar granular layer.SIGNIFICANCE STATEMENT This article shows for the first time a novel form of Ca²⁺ channel-dependent synaptic plasticity at the excitatory synapses impinging on cerebellar Golgi cells. This plasticity is bidirectional and inverted with respect to NMDA receptor-dependent paradigms, with long-term depression (LTD) and long-term potentiation (LTP) being favored at depolarized and hyperpolarized potentials, respectively. Furthermore, LTP and LTD induction requires differential involvement of T-type and L-type voltage-gated Ca²⁺ channels rather than the NMDA receptors alone. These results, along with recent computational predictions, support the idea that Golgi cell plasticity could play a crucial role in controlling information flow through the granular layer along with cerebellar learning and memory.     

Regulation and Interaction of Multiple Types of Synaptic Plasticity in a Purkinje Neuron and Their Contribution to Motor Learning

There are multiple types of plasticity at both excitatory glutamatergic and inhibitory GABAergic synapses onto a cerebellar Purkinje neuron (PN). At parallel fiber to PN synapses, long-term depression (LTD) and long-term potentiation (LTP) occur, while at molecular layer interneuron to PN synapses, a type of LTP called rebound potentiation (RP) takes place. LTD, LTP, and RP seem to contribute to motor learning. However, each type of synaptic plasticity might play a different role in various motor learning paradigms. In addition, defects in one type of synaptic plasticity could be compensated by other forms of synaptic plasticity, which might conceal the contribution of a particular type of synaptic plasticity to motor learning. The threshold stimulation for inducing each type of synaptic plasticity and the induction conditions are different for different plasticity mechanisms, and they change depending on the state of an animal. Facilitation and/or saturation of synaptic plasticity occur after certain behavioral experiences or in some transgenic mice. Thus, the regulation and roles of synaptic plasticity are complicated. Toward a comprehensive understanding of the respective roles of each type of synaptic plasticity and their possible interactions during motor learning processes, I summarize induction conditions, modulations, interactions, and saturation of synaptic plasticity and discuss how multiple types of synaptic plasticity in a PN might work together in motor learning processes.     

Agonists of cholinergic and noradrenergic receptors facilitate synergistically the induction of long-term potentiation in slices of rat visual cortex.

Acetylcholine (ACh) and noradrenaline (NA) have been shown to facilitate experience-dependent modifications of synaptic connectivity during postnatal development of the kitten visual cortex. To further investigate the mechanisms of this facilitation we studied the effects of these neuromodulators in an in vitro model of use-dependent synaptic plasticity. We have chosen long-term potentiation (LTP) in rat visual cortex slices because it shares several features with the in vivo model. In both cases induction of synaptic modifications requires that postsynaptic activation reaches a critical threshold and in both cases changes are induced more easily in young animals and when N-methyl-D-aspartate (NMDA) receptor-gated conductances are activated. Intracellular recordings were obtained from regular spiking cells in supragranular layers of rat visual cortex and LTP was induced by tetanic stimulation of the underlying white matter. Both cholinergic and noradrenergic agonists raised the probability that tetanic stimuli induced LTP and as in vivo they acted synergistically. These effects were mediated by agonists of muscarinic and beta-receptors, respectively. The agonists of both receptor systems enhanced the depolarizing response to the tetanus and increased NMDA receptor-gated conductances during this response. We suggest that this mode of action also accounts for the facilitatory effects which ACh and NA have on use-dependent synaptic plasticity in the developing visual cortex.     

NMDA Receptor-dependent LTD in different subfields of hippocampus in vivo and in vitro

In simulations with artificial neural networks, efficient information processing and storage has been shown to require that the strength of connections between network elements has the capacity to both increase and decrease in a use-dependent manner. In contrast to long-term potentiation (LTP) of excitatory synaptic transmission, activity-dependent long-term depression (LTD) has been difficult to demonstrate in forebrain in vivo. Theoretical arguments indicate that coincidence of presynaptic excitation and low-magnitude postsynaptic activation are the necessary prerequisites for LTD induction. Here we report that stimulation paradigms which cause 1) sufficient excitation to result in NMDA receptor activation and simultaneously 2) attenuate the level of postsynaptic activation by recruitment of GABA_A receptor-mediated inhibition consistently produce LTD of commissural input to area CA1 in the hippocampus of anesthetized adult rats, and of the perforant path input to the dentate gyrus in the hippocampus of anesthetized and unanesthetized adult rabbits. A functionally similar pre- and postsynaptic activation pattern applied to the hippocampal slice preparation by injecting hyperpolarizing current into the postsynaptic cell during NMDA receptor-mediated excitation also was effective in consistently inducing LTD. Results of studies in vitro show that Ca²⁺ influx through the NMDA channel is necessary for the induction of LTD, and moreover, that NMDA receptors also participate in the expression of LTD. Our findings demonstrate a general mechanism for the implementation of a theoretically derived learning rule in adult forebrain in vivo and in vitro and provide justification for the inclusion of use-dependent decreases of connection weights in formal models of cognitive processing. © 1996 Wiley-Liss, Inc.     

Repetition of mGluR-dependent LTD causes slowly developing persistent reduction in synaptic strength accompanied by synapse elimination

Synaptic plasticity, the cellular basis of memory, operates in a bidirectional manner. LTP (long-term potentiation) is followed by structural changes that may lead to the formation of new synapses. However, little is known whether LTD (long-term depression) is followed by morphological changes. Here we show that the repetitive induction of metabotropic glutamate receptor (mGluR)-dependent LTD in stable cultures of rat hippocampal slices led to a slowly developing persistent (ranging over weeks) reduction in synaptic strength that was accompanied by the loss of synaptic structures. LTD was induced pharmacologically 1-3 times at 24-h intervals by applying aseptically ACPD (1-aminocyclopentane-1,3-dicarboxylic acid), an agonist of group I/II mGluR, and APV (2-amino-5-phosphonovalerate), an antagonist of the NMDA (N-methyl-D-aspartate) receptor. One ACPD/APV application induced LTD that lasted less than 24 h. After three LTD inductions, however, a gradual attenuation of the fEPSP (field excitatory postsynaptic potential) amplitude and a decrease in the number of pre- and postsynaptic structures were observed. The blockade of LTD by an mGluR antagonist or a protein phosphatase 2B inhibitor abolished the development of the synaptic attenuation. In contrast to our previous finding that the repetitive LTP induction triggered a slowly developing persistent synaptic enhancement, the incremental and decremental forms of synaptic plasticity appeared to occur symmetrically not only on the minutes-hours time order but also on the days-weeks time order.     

Interleukin-6 inhibits long-term potentiation in rat hippocampal slices

The effects of recombinant human interleukin-6 (rhIL-6) on long-term potentiation (LTP) induced in the Schaffer collateral/commissural-CA1 pathway were examined using rat hippocampal slices. Field excitatory postsynaptic potential was recorded in the stratum radiatum of the CA1 region. Ten-min applications of rhIL-6 (50–2000 U/ml), started 5 min before the tetanus, significantly inhibited the induction of LTP, and in high doses of rhIL-6 also inhibited short-term potentiation (over 200 U/ml) and post-tetanic potentiation (over 500 U/ml). The effects of rhIL-6 (500 U/ml) were completely abolished by the preincubation of the slices with monoclonal anti-IL-6 receptor antibody (16 μg/ml) for 2 h. Heat-inactivated rhIL-6 had no effect on the synaptic potentiation. RhIL-6 affected neither the previously established LTP nor the basal synaptic transmission. These findings indicated that rhIL-6 modulated synaptic potentiation through the IL-6 receptor-mediated process in the hippocampus, probably by affecting post- and presynaptic sites in the CA1 region. The possible mechanisms of the IL-6-induced suppression of the synaptic potentiation were discussed.     

Hippocampal long-term depression is enhanced, depotentiation is inhibited and long-term potentiation is unaffected by the application of a selective c-Jun N-terminal kinase inhibitor to freely behaving rats

Synaptic plasticity is regarded as the major candidate mechanism for synaptic information storage and memory formation in the hippocampus. Mitogen‐activated protein kinases have recently emerged as an important regulatory factor in many forms of synaptic plasticity and memory. As one of the subfamilies of mitogen‐activated protein kinases, extracellular‐regulated kinase is involved in the in vitro induction of long‐term potentiation (LTP), whereas p38 mediates metabotropic glutamate receptor‐dependent long‐term depression (LTD) in vitro. Although c‐Jun N‐terminal kinase (JNK) has also been implicated in synaptic plasticity, the in vivo relevance of JNK activity to different forms of synaptic plasticity remains to be further explored. We investigated the effect of inhibition of JNK on different forms of synaptic plasticity in the dentate gyrus of freely behaving adult rats. Intracereboventricular application of c‐Jun N‐terminal protein kinase‐inhibiting peptide (D‐JNKI) (96 ng), a highly selective JNK inhibitor peptide, did not affect basal synaptic transmission but reduced neuronal excitability with a higher dose (192 ng). Application of D‐JNKI, at a concentration that did not affect basal synaptic transmission, resulted in reduced specific phosphorylation of the JNK substrates postsynaptic density 95kD protein (PSD 95) and c‐Jun, a significant enhancement of LTD and a facilitation of short‐term depression into LTD. Both LTP and short‐term potentiation were unaffected. An inhibition of depotentiation (recovery of LTP) occurred. These data suggest that suppression of JNK‐dependent signalling may serve to enhance synaptic depression, and indirectly promote LTP through impairment of depotentiation.     

Selective modulation of Ca(2+) influx pathways by 5-HT regulates synaptic long-term plasticity in the hippocampus

Both long-term potentiation (LTP) and long-term depression (LTD) can be induced in the Schaffer collateral-CA1 synapse of the hippocampus either by repetitive stimulation of afferent fibres with the frequency of the stimulation determining the polarity of the response or by associative pairing of pre- and postsynaptic activity. An increase in postsynaptic intracellular Ca(2+) concentration is an important signal for the induction of long-term synaptic plasticity. In patch-clamp experiments on hippocampal brain slices, we tested the modulation of different forms of synaptic plasticity by the neurotransmitter serotonin (5-HT) which is known to inhibit high-voltage activated Ca(2+) channels. 1 microM of 5-HT inhibited homosynaptic LTD induced by low frequency stimulation. This effect of 5-HT could be blocked by the selective 5-HT(1A) antagonist WAY 100635. Low frequency-induced LTD is both dependent on Ca(2+) influx through NMDA receptors and high-voltage activated Ca(2+) channels. It was blocked by the NMDA-receptor antagonist D-AP5 and by the N-type Ca(2+) channel antagonist omega-conotoxin GIVA. Tetanus induced LTP was not affected by low concentrations of 5-HT, whereas depotentiation of LTP by asynchronous pairing of EPSPs and postsynaptic action potentials was completely abolished with 5-HT in the bath solution. We conclude that those forms of plasticity which depend on Ca(2+) influx via high-voltage activated Ca(2+) channels are subject to modulation by 5-HT. This might be a relevant mechanism by which 5-HT modifies basic network properties in the brain.     

Adenosine depresses induction of LTP at the mossy fiber-CA3 synapse in vitro

Using the hippocampal slice preparation, extracellular recordings of CA3 field excitatory postsynaptic potentials (fEPSPs) were performed to assess the effects of adenosine on the induction of mossy fiber long-term potentiation (LTP). When present during tetanization, adenosine (50 μM) significantly suppressed mossy fiber LTP whereas it failed to inhibit LTP when applied immediately after high-frequency stimulation. Based on the hypothesis that mossy LTP is presynaptic in origin, our data thus provide first evidence that adenosine's presynaptic action alone is sufficiently powerful to interfere with synaptic plasticity.