Spatial and emotional memory in aged rats: a behavioral-statistical analysis.

Age-related impairment in synaptic plasticity, like long-term potentiation (LTP), has been repeatedly reported. We had shown that late stages of LTP in the rat dentate gyrus can be modulated by emotional factors, but this is impaired by aging. In the present study we have searched for possible impairments in emotional and spatial memory tasks that may correspond to the impaired reinforcement observed at the cellular level. We have trained young and aged animals in a battery of tests: exploration (open field) object recognition, anxiety (plus maze) fear conditioning and spatial memory (Morris' water maze (MWM)). The open field, anxiety, and novelty recognition showed no age differences except a reduced velocity in aged rats. Emotional and contextual memories were preserved, but acquisition was slightly impaired. Age-dependent impairments appeared in spatial memory, evaluated in terms of latency and distance to reach the hidden escape platform in the water maze task, but these were not related with impairments in other tests, in particular there was no relation between spatial and emotional memory impairments. Age-related impairments in different paradigms were caused by different independent factors that did not correlated with each other.

Properties of subsequent induction of long-term potentiation and/or depression in one synaptic input in apical dendrites of hippocampal CA1 neurons in vitro.

The hippocampus is a prominent structure to study mechanisms of learning and memory at the cellular level. Long-term potentiation (LTP) as well as long-term depression (LTD) are the major cellular models which could underlie learning and memory formation. LTP and LTD consist of at least two phases, an early protein synthesis-independent transient stage (<4 h; E-LTP, E-LTD) as well as a prolonged phase (>4 h; L-LTP, L-LTD) requiring the synthesis of new proteins. It is known that during E-LTP the further induction of longer lasting LTP is precluded. However, if E-LTP is transformed into L-LTP, the same synapses now allow the induction of LTP again. We reproduced the LTP-results first and then investigated whether hippocampal LTP or LTD also prevents the establishment of subsequent LTD-induction in the same synaptic input. We show that the prior induction of LTP or LTD does not prevent a short-term depression (STD) but occludes LTD in apical dendrites of CA1 neurons in hippocampal slices in vitro during the early phase of LTP or LTD. However, LTD can again be induced in addition to STD after the establishment of L-LTP or L-LTD, that is about 4 h after the induction of the first event in the same synaptic input. We suggest that the neuronal input preserves the capacity for STD immediately after an initial potentiation or depression, but for the onset of additional longer lasting LTD in the same synaptic input, the establishment of the late plasticity form of the preceding event is critical.

Basolateral amygdala stimulation does not recruit LTP at depotentiated synapses.

Hippocampal long-term potentiation (LTP) is a long-lasting increase in synaptic efficacy considered to be the cellular basis of memory. LTP consists of an early, protein synthesis-independent phase (E-LTP) and a late phase that depends on protein synthesis (L-LTP). Application of a weak tetanus can induce E-LTP in the dentate gyrus (DG) which can be reinforced into L-LTP by direct stimulation of the basolateral amygdala (BLA) within 30 min before or after LTP induction (structural LTP-reinforcement). LTP can be depotentiated by low-frequency stimulation (LFS) to the same synaptic input if applied shortly after tetanization (<10 min). Here, we addressed the question of whether stimulation of the BLA is able to recover LTP at depotentiated synaptic inputs. We hypothesized that E-LTP can activate synaptic tags, which were then reset by depotentiation. Stimulation of the BLA thereafter could beneficially act on tag-reactivation as well as on the activation of the synthesis of plasticity-related proteins (PRPs), normally captured by the tags and thus transforming E-LTP into L-LTP. Our results show, that BLA-stimulation was not able to reactivate the resetting of tags by depotentiation in the DG of freely moving rats.

Protein degradation by the proteasome is required for synaptic tagging and the heterosynaptic stabilization of hippocampal late-phase long-term potentiation.

Activity-dependent regulation of synaptic efficacy is believed to underlie learning and memory formation. Here we show that protein degradation by the proteasome is required for the induction of the protein synthesis-dependent late-phase of long-term potentiation (late-LTP) but not for its maintenance. Proteasome activity was also key to the polarity of heterosynaptic interactions between synapses expressing synaptic plasticity and newly activated synapses. In fact, proteasome activity was required for the consolidation of an otherwise transient potentiation (early-LTP) into late-LTP by strong tetanization of a separate afferent pathway both in the "weak-before-strong" and in the "strong-before-weak" two-pathway paradigms [Frey and Morris (1997) Nature 385:533-536; Frey and Morris (1998) Neuropharmacology 37:545-552], suggesting that proteasome activity plays a role in the synaptic tagging and capture of plasticity-related proteins at stimulated synapses. Additionally, proteasome inhibition abrogated immunity against heterosynaptic depotentiation of an established late-LTP when applied during weak tetanic stimulation in the "strong-before-weak" two-pathway paradigm. Such a heterosynaptic destabilizing effect of proteasome inhibition was abolished by concomitant inhibition of N-methyl-d-aspartate (NMDA) receptors, suggesting that it is an active process. Together, these results indicate that the proteasome plays important roles in the establishment of late-LTP and in the preservation of potentiated synapses when a subsequent synaptic plasticity is induced within the same neuronal population.

Electrical and pharmacological manipulations of the nucleus accumbens core impair synaptic plasticity in the dentate gyrus of the rat.

The interest on the physiology of the nucleus accumbens (NAcc) has grown in recent years given its relationship to addictive behaviours, and the possibility to treat them by interacting with NAcc function. We have shown that the prior stimulation of the core region blocks induction of long-term potentiation (LTP) at the dentate gyrus in anaesthetized rats, while the shell facilitated it. In the present study we have confirmed and expanded those results testing the effects of core and shell stimulation in freely moving rats, as well as the effect of blocking D1 receptors in the NAcc. Our results show that shell stimulation had no effect on baseline recordings of the field excitatory postsynaptic potential (fEPSP) or the population spike amplitude (PSA) for 24 h. Core stimulation did not modify baseline-fEPSP, but significantly depressed PSA up to 8 h. LTP maintenance was not modified; neither by core nor shell stimulation after its induction, but LTP induction was impaired (both in the fEPSP and PSA) by core stimulation 15 min before induction. Shell stimulation showed a slight facilitating effect. Previous, topical application of a dopaminergic-receptor antagonist (SCH23390) into the NAcc produced a significantly depressed baseline fEPSP and PSA, as well as LTP measured in both components of the evoked potentials. Our results confirm a dual role of stimulation of NAcc sub-regions on hippocampal baseline synaptic transmission, and LTP induction when activated before induction. In contrast, stimulation of the NAcc had no influence on an already ongoing dentate gyrus LTP. A role for dopaminergic innervation to the NAcc, modifying susceptibility for synaptic plasticity outside the NAcc is also suggested by our results.

Continuous blockade of GABA-ergic inhibition induces novel forms of long-lasting plastic changes in apical dendrites of the hippocampal cornu ammonis 1 (CA1) in vitro.

Hippocampal long-term potentiation (LTP) is considered as a fundamental mechanism for learning and memory formation. A role for GABA was reported for the induction and early but not late maintenance of LTP. We have now investigated whether GABA-receptor function is involved in the prolonged maintenance of LTP (>4 h) at afferent synapses at apical dendrites of cornu ammonis 1 (CA1)-pyramidal neurons in hippocampal slices in vitro. Our data demonstrate that GABA-receptor mediated events are not required for conventional, tetanically-induced early- or late-LTP in the hippocampal CA1-region in vitro. Inhibition of GABA-ergic transmission did not negatively influence either early- or late-LTP. In contrast, an additional facilitation was observed at time points corresponding to the establishment of late-LTP (after 3-4 h). Investigation of a second, non-tetanized control input to the same neuronal population revealed that the elevated potentiation of late-LTP in the tetanized input was not LTP-specific. Therefore, we have examined, whether continuous application of GABA-receptor inhibitors also affected the time course of the recorded potentials when a low-frequency stimulation protocol was used. Under these conditions two distinct forms of a late-onset potentiation occurred 5-6 h after drug application. Investigation of mechanisms responsible for this prolonged enhancement of potentials revealed that the higher form of potentiation (potentiation levels above 200%) was dependent on presynaptic activity and N-methyl-d-aspartate (NMDA)-receptor activation, whereas the lower form (potentiation less than 200%) did not require these mechanisms. However, the latter potentiation was prevented by nifedipine, an L-type voltage-dependent calcium channel inhibitor.

Differential effects of electrical stimulation patterns, motivational-behavioral stimuli and their order of application on functional plasticity processes within one input in the dentate gyrus of freely moving rats in vivo.

Hippocampal long-term potentiation (LTP) is a long-lasting increase in synaptic efficacy considered to be the cellular basis of memory. LTP consists of an early, protein synthesis-independent phase (E-LTP) and a late phase that depends on protein synthesis (L-LTP). In water-deprived rats E-LTP in the dentate gyrus (DG) can be reinforced into L-LTP, if the rats were allowed to drink within 15 min after E-LTP induction (behavioral LTP-reinforcement, BR). LTP can be depotentiated by low-frequency stimulation (LFS) to the same synaptic input if applied shortly after tetanization (<10 min). Here, we addressed the question of whether a BR protocol is able to recover LTP at depotentiated synaptic inputs. We show that LTP, depotentiation, LFS and BR specifically interact within one afferent input, which could be explained by the "synaptic tagging" hypothesis outlined by [Frey and Morris (1997) Nature 385:533-536]. E-LTP induced by a weak tetanus (WTET) sets tags in the activated inputs which are able to capture and to process plasticity-related proteins (PRPs) required for L-LTP, the synthesis of which was induced by BR. Synaptic tags could be reset by LFS. BR alone was unable to rescue depotentiated LTP, but the combination of BR and subsequent WTET transformed E-LTP into L-LTP. We show that LTP, LTD and behavioral stimuli alternatively and reversibly affect a single afferent input for long periods of time by LTP as well as LTD mechanisms, competing with each other under the influence of different concurrent stimuli. Affective modulation can shift the balance to one or the other. We show that the result will depend not only on the last stimulus, but on the history of previous stimuli applied to the specific input. Afferent stimuli activate alternative, but partially overlapping cascades with long-lasting consequences for the input including spaced-associative processes of "synaptic tagging" as well as "cross-tagging" which could be demonstrated in single synaptic afferents to one neuronal population in freely behaving animals.

Maternal separation during a specific postnatal time window prevents reinforcement of hippocampal long-term potentiation in adolescent rats.

In an attempt to develop an animal model to study the etiology of brain dysfunction in relation to early life experience, we tested the hypothesis that early-life stress during specific postnatal time windows affects long-term potentiation (LTP) reinforcement in adolescence. Male Wistar rat pups were stressed by separation from their dams for 24 h at postnatal day (PND) 4, 9, or 18. The animals were tested for reinforcement of LTP at adolescence (9 weeks old) by exposing them to a 2-min swim-stress. Here, we show that maternal separation during (at PND9) but not at the beginning (at PND4) or after (at PND18) the stress-hyporesponsive-period of the hypothalamic-pituitary-adrenal-axis impairs emotional LTP-reinforcement in adolescent animals. Thus, this in vivo model allows the investigation of physiological and pathophysiological emotional information processing at the cellular level in freely behaving adolescent animals.

Opposite effects of shell or core stimulation of the nucleus accumbens on long-term potentiation in dentate gyrus of anesthetized rats.

Hippocampal long-term potentiation (LTP) is a long-lasting increase in synaptic efficacy which is considered a cellular correlate of learning and memory. It has been shown that both, stimuli with emotional/motivational content and the electrical stimulation the basolateral amygdala, can modulate hippocampal LTP. The nucleus accumbens is part of the ventral striatum and is composed of two main regions: core and shell. Core and shell share a similar cellular composition, but differ in their connectivity with other brain areas. Considering that the nucleus accumbens is related to motivation and that it receives a strong projection from the basolateral amygdala, we have studied the effect of stimulating accumbens shell or core on medial perforant path-granule cells' LTP in anesthetized male Wistar rats. We found that electrical stimulation of the shell enhances the magnitude of LTP while the stimulation of the core completely prevents LTP induction. The stimulation of the accumbens shell or core alone produced no apparent, direct field potential in dentate gyrus. Additionally, the co-stimulation of the shell or core with the medial perforant path does not modify the input-output curves obtained using stimulation of the perforant path only. These results demonstrate that electrical stimulation of the accumbens shell or core has a bidirectional effect on LTP induction at the dentate gyrus.

Subcortical deafferentation impairs behavioral reinforcement of long-term potentiation in the dentate gyrus of freely moving rats.

Long-term potentiation is a form of neural functional plasticity which has been related with memory formation and recovery of function after brain injury. Previous studies have shown that a transient early-long-term potentiation can be prolonged by direct stimulation of distinct brain areas, or behavioral stimuli with a high motivational content. The basolateral amygdala and other subcortical structures, like the medial septum and the locus coeruleus, are involved in mediating the reinforcing effect. We have previously shown that the lesion of the fimbria-fornix--the main entrance of subcortical afferents to the hippocampus--abolishes the reinforcing basolateral amygdala-effects on long-term potentiation in the dentate gyrus in vivo. It remains to be investigated, however, if such subcortical afferents may also be important for behavioral reinforcement of long-term potentiation. Young-adult (8 weeks) Sprague-Dawley male rats were fimbria-fornix-transected under anesthesia, and electrodes were implanted at the dentate gyrus and the perforant path. One week after surgery the freely moving animals were studied. Fimbria-fornix-lesion reduced the ability of the animals to develop long-term potentiation when a short pulse duration was used for tetanization (0.1 ms per half-wave of a biphasic stimulus), whereas increasing the pulse duration to 0.2 ms per half-wave during tetanization resulted in a transient early-long-term potentiation lasting about 4 h in the lesioned animals, comparable to that obtained in non-lesioned or sham-operated control rats. In water-deprived (24 h) control animals, i.e. in non-lesioned and sham-operated rats, early-long-term potentiation could be behaviorally reinforced by drinking 15 min after tetanization. However, in fimbria-fornix-lesioned animals long-term potentiation-reinforcement by drinking was not detected. This result indicates that the effect of behavioral-motivational stimuli to reinforce long-term potentiation is mediated by subcortical, heterosynaptic afferents.

Phosphodiesterase 4B (PDE4B) and cAMP-level regulation within different tissue fractions of rat hippocampal slices during long-term potentiation in vitro.

Molecular events associated with mnemonic processes and neuronal plasticity are postulated to result in functional changes in synaptic structure. One possible site is the post-synaptic density, where activity-dependent changes modulate signal transduction cascades. In this report, we detail spatial-temporal changes for phosphodiesterase 4B (PDE4B) proteins and their substrate cAMP within three neuronal fractions during early and late long-term potentiation (LTP). The cAMP-dependent protein kinase A cascade--which can be regulated by distinct PDE4B activity--is required for mnemonic processes as well as mechanisms of neuronal plasticity, such as those during the maintenance or late-LTP. Fluorescence in situ hybridization studies (FISH) identified no translocation of PDE4B3 from the soma after late-LTP induction indicating a subtle, local control of PDE4B activity. Protein changes were detected within the PSD-enriched fraction. From these results, we conclude that either the changes in PDE4B are due to modulation of pre-existing mRNA, or that the protein is specifically translocated to activated synaptic structures. Furthermore, we report late changes in cAMP levels in the somato-dendritic fraction and discuss this result with the increased PDE4B1/3 doublet in the PSD-enriched fraction.

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.

Effect of LTP-reinforcing paradigms on neurotransmitter release in the dentate gyrus of young and aged rats.

Long-term potentiation (LTP) is considered a cellular correlate of memory processing. A short-lasting early-LTP can be prolonged into a late-L TP (>4h) by stimulation of the basolateral amygdala (BLA) or motivational behavioral stimuli in young, but not in aged, cognitively impaired rats. We measured the changes in transmitter release-induced by BLA or behavioral reinforcement-in young and aged cognitively impaired rats, after implanting a microdialysis cannula at the dentate gyrus. Samples were taken under baseline conditions and during stimulation of BLA. Rats were water deprived and tested again next day, taking samples after allowing access to water. Higher concentrations of choline, HIAA, aspartate, glutamate, and glycine were found in baseline samples from young animals compared to aged. In young animals, BLA stimulation increased the levels of ACh and reduced norepinephrine and serotonine, while behavioral reinforcement reduced the levels of glutamate and glycine. These effects were absent among aged rats, suggesting that this reduced neurochemical response might be linked to the impaired LTP-reinforcement reported previously.

Resetting of 'synaptic tags' is time- and activity-dependent in rat hippocampal CA1 in vitro.

We have recently proposed that the maintenance of hippocampal long-term potentiation (LTP) and depression depends on at least two required processes: induction of LTP must set (1) process-specific 'synaptic tags' which capture (2) process-unspecific plasticity-related proteins (PRPs), synthesized via a heterosynaptic interaction [Neurobiol Learn Mem 82 (2004) 12]. The 'tag' as well as the PRPs are characterized by a relatively short half-life of several minutes up to a few hours before they degrade most likely by processes such as dephosphorylation. The question now arose whether the 'tags' can also be reset in an activity-dependent manner, thus preventing the processing of PRPs with the result of transient short-lasting plasticity. Here we have investigated this topic during early-LTP and found that low-frequency stimulation shortly after early-LTP-induction (5 min) resets the 'tag' or the 'tag complex' of macromolecules preventing any lasting forms of LTP and thus, preventing the formation of a memory trace.

Regulation of the phosphodiesterase PDE4B3-isotype during long-term potentiation in the area dentata in vivo.

Hippocampal long-term potentiation (LTP) is the most prominent cellular model underlying learning and memory formation. However, which cellular processes are involved in maintaining LTP remains largely unknown. We have previously detailed temporal modulations of cyclic adenosine monophosphate (cAMP) and a cAMP-specific phosphodiesterase, PDE4B3, after LTP-induction and its maintenance in hippocampal area CA1 in vitro. To test whether other hippocampal sub-structures are characterised by similar mechanisms, tissue from the area dentata of freely moving rats was analysed at different LTP-time points. The tissue was fractionated into three components, where PDE4B-levels and cAMP-concentrations were measured. In contrast with data obtained in area CA1, we now detail an LTP-specific translational, but not transcriptional regulation of PDE4B3 within the first 8 h after tetanization and present spatio-temporal changes of PDE4B proteins and cAMP that is LTP-specific.

Modulation of late phases of long-term potentiation in rat dentate gyrus by stimulation of the medial septum.

The prolonged maintenance of hippocampal long-term potentiation (LTP) seems to require heterosynaptic events during its induction. We have previously shown that stimulation of the basolateral nucleus of the amygdala (BLA) within a distinct time window can reinforce a transient early-LTP into a long-lasting late-LTP in the dentate gyrus (DG) in freely moving rats. We have shown that this reinforcement was dependent on beta-adrenergic and/or muscarinergic receptor activation and protein synthesis. However, since the BLA does not directly stimulate the DG the question remained by which inputs such heterosynaptic processes are triggered. We have now directly stimulated the medial septal pathway 15 min after induction of early-LTP in the DG and show that this input is capable of reinforcing early into late-LTP in a frequency-dependent manner. This septal reinforcement of DG LTP was dependent on beta-adrenergic receptor activation and protein synthesis. We suggest that the reinforcing effect of the BLA stimulation can, potentially, be mediated via the septal input to the DG, though it differs in its ability to induce or modulate functional plasticity.

The amygdala is part of the behavioural reinforcement system modulating long-term potentiation in rat hippocampus.

Long-term potentiation (LTP) in the dentate gyrus can be modulated and prolonged by emotional/motivational influences when concurrently activated. A similar effect on LTP can be obtained by stimulating the amygdala, suggesting that this limbic structure might be part of the neural system involved in behavioural reinforcement. To confirm this we have performed a series of experiments in which the basolateral amygdala was either temporary inactivated by injection of lidocaine or permanently lesioned electrolytically. Both manipulations completely blocked the reinforcing effect of a motivational stimulus (drinking after 24-h deprivation) on LTP at the perforant pathway-dentate gyrus synapses, whilst leaving intact the non-reinforced potentiation. These results demonstrate that the basolateral amygdala is a key structure within the system involved in the modulatory interaction between the affective status of the animal and the mechanisms of functional plasticity.

Involvement of beta-adrenergic receptors in protein synthesis-dependent late long-term potentiation (LTP) in the dentate gyrus of freely moving rats: the critical role of the LTP induction strength.

We have investigated the requirement of beta-adrenergic receptor activation and protein synthesis for the induction and specifically for the maintenance of long-term potentiation (LTP) in the dentate gyrus of freely moving rats in dependency on different LTP-induction procedures. Three tetanization paradigms were used: a relatively weak protocol A (10 bursts of 15 biphasic pulses at 200 Hz; 10-s interburst interval; 0.2-ms pulse width per phase), a stronger protocol B (as protocol A but 20 bursts and 0.25-ms pulse width) and, as the strongest condition, protocol C (2 times protocol B; inter-tetanus interval: 5 min). All protocols led to robust late-LTP in control animals. Late- but not early-LTP was protein synthesis-dependent under all tetanization conditions as indicated by the absence of long-lasting LTP when the protein synthesis inhibitor anisomycin was applied before tetanization. Application of the beta-adrenergic receptor antagonist propranolol before LTP induction prevented late-LTP when either protocol A or B but not when protocol C was used. Thus, repeated strong tetanization can compensate for the loss of beta-adrenergic receptor activation. We suggest that the results could provide a link to cellular mechanisms of memory consolidation in respect to the strength and relevance of the incoming sensory information during learning.

Expression of the specific type IV phosphodiesterase gene PDE4B3 during different phases of long-term potentiation in single hippocampal slices of rats in vitro.

Hippocampal long-term potentiation (LTP), the most prominent cellular model for learning and memory formation, consists of phases: early-LTP (<4 h) and late-LTP (>4 h), with the latter dependent upon protein translation and transcription. To explore the molecular processes that might be specifically regulated during late-LTP, we have modified standard electrophysiological and molecular biological methods, which allowed the cloning of activated genes and their products from single hippocampal slices in vitro 8 h after LTP induction. From one such screen we identified a specific type IV phosphodiesterase gene, PDE4B3, the first cAMP-specific phosphodiesterase to be associated with LTP. Previous studies documented an integral role for the cAMP-PKA system in late-LTP and recently, inhibition of cAMP degradation facilitates LTP and ameliorates mnemonic deficits. We now report that PDE4B3 is modulated during LTP phases. Its activation is NMDA-receptor dependent and its transcription is transiently up-regulated 2 h after tetanization. Protein expression peaks 6 h after LTP induction and is rapidly down-regulated at 8 h, whereas cAMP levels decrease during LTP phases. Immunohistochemical studies identified that the majority of type IV phosphodiesterase protein staining is localized to the cell bodies and dendrites of neurones in hippocampal CA1.

Quantal analysis suggests strong involvement of presynaptic mechanisms during the initial 3 h maintenance of long-term potentiation in rat hippocampal CA1 area in vitro.

Long-term potentiation (LTP) is the most prominent model to study neuronal plasticity. Previous studies using quantal analysis of an early stage of LTP in the CA1 hippocampal region (<1 h after induction) suggested increases in both the mean number of transmitter quanta released by each presynaptic pulse (m, quantal content) and postsynaptic effect of a single quantum (v, quantal size). When LTP was large, it was m that increased predominantly suggesting prevailing presynaptic contribution. However, LTP consists of several temporary phases with presumably different mechanisms. Here we recorded excitatory postsynaptic potentials from CA1 hippocampal slices before and up to 3.5 h after LTP induction. A new version of the noise deconvolution revealed significant increases in m with smaller and often not statistically significant changes in v. The changes in m were similar for both early (<1 h) and later (1-3 h) post-tetanic periods and correlated with LTP magnitude. The coefficient of variation of the response amplitude and the number of failures decreased during both early and late post-tetanic periods. The results suggest that both early (<0.5 h) and later LTP components (0.5-3 h) are maintained by presynaptic changes, which include increases in release probabilities and the number of effective release sites. In addition initially silent synapses can be converted into effective ones due to either pre- or postsynaptic rearrangements. If this occurs, our data indicate that the number and the efficacy of the receptors in the new transmission sites are approximately similar to those in the previously effective sites.