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J U Frey

Publications and source records attributed to J U Frey.

17 recordsLinked to original sources
PubMed2006

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.

Afferent Pathways↗
PubMed2005

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.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2005

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.

Acetylcholine↗
PubMed2005

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.

Animals↗
PubMed2004

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.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2004

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.

Animals↗
PubMed2003

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.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2003

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.

Amygdala↗
PubMed2003

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.

Adrenergic beta-Antagonists↗
PubMed2003

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.

Adrenergic beta-Antagonists↗
PubMed2002

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.

Animals↗
PubMed2001

Reinforcement of early long-term potentiation (early-LTP) in dentate gyrus by stimulation of the basolateral amygdala: heterosynaptic induction mechanisms of late-LTP.

The basolateral amygdala (BLA) can influence distinct learning and memory formation. Hippocampal long-term potentiation (LTP), the most prominent cellular model of memory formation, can be modulated by stimulation of the BLA in its induction and early maintenance. However, it is not known how the late maintenance of LTP beyond its initial phases might be affected. Behavioral stimuli have been shown to result in a reinforcement of a transient early-LTP into a lasting potentiation. Here we show that BLA stimulation mimics the behavioral effects on early-LTP in freely moving rats when the BLA is activated within a time window of 30 min before or after tetanization of the perforant path. The reinforcement of LTP was blocked by inhibitors of muscarinergic and beta-adrenergic but not dopaminergic receptors and was dependent on translation. Through these heterosynaptic associative interactions, hippocampal sensory information can be stabilized by amygdaloidal influences.

Adrenergic beta-Antagonists↗
PubMed2001

Behavioral reinforcement of long-term potentiation is impaired in aged rats with cognitive deficiencies.

Behavioral stimuli with emotional/motivational content can reinforce long-term potentiation in the dentate gyrus, if presented within a distinct time window. A similar effect can be obtained by stimulating the basolateral amygdala, a limbic structure related to emotions. We have previously shown that aging impairs amygdala-hippocampus interactions during long-term potentiation. In this report we show that behavioral reinforcement of long-term potentiation is also impaired in aged rats with cognitive deficits. While among young water-deprived animals drinking 15 min after induction of long-term potentiation leads to a significant prolongation of potentiation, cognitively impaired aged rats are devoid of such reinforcing effects. In contrast, a slight but statistically significant depression develops after drinking in this group of animals. We suggest that an impaired mechanism of emotional/motivational reinforcement of synaptic plasticity might be functionally related to the cognitive deficits shown by aged animals.

Aging↗
PubMed2000

Requirement of translation but not transcription for the maintenance of long-term depression in the CA1 region of freely moving rats.

Hippocampal long-term depression (LTD) comprises a persistent reduction in synaptic strength that can be induced in the CA1 region by repeated low-frequency stimulation (LFS). Previous studies have demonstrated that hippocampal long-term potentiation requires de novo protein synthesis. Whether hippocampal LTD is also protein synthesis-dependent is not known. In this study, we investigated if the previous administration of translation inhibitors (anisomycin or emetine) or a transcription inhibitor (actinomycin-D) influenced the profile of LTD in freely moving adult Wistar rats. Seven- to 8-week-old animals underwent chronic implantation of a recording electrode in the CA1 stratum radiatum and a stimulation electrode in the Schaffer collateral/commissural fiber pathway. A cannula was implanted in the ipsilateral cerebral ventricle to enable drug administration. Experiments were commenced 10 d after the implantation procedure. Immediately after application of LFS (1 Hz, 900 pulses) robust LTD was seen that persisted for >8 hr in control animals. Application of anisomycin (240 microg/5 microl) emetine (240 microg/5 microl) before LFS prevented the expression of LTD or approximately 4.5 hr after LFS. Previous administration of actinomycin D (72 microg/12 microl) had no effect on the expression of LTD. None of the compounds elicited significant effects on basal synaptic transmission when administered in the absence of LFS. These data suggest that LTD in the CA1 region in vivo is protein synthesis-dependent. Furthermore, persistent LTD can be established through the translation of existing mRNA, whereas de novo mRNA transcription does not appear to be necessary.

Animals↗
PubMed2000

Lesioning the fimbria-fornix impairs basolateral amygdala induced reinforcement of LTP in the dentate gyrus.

We have recently shown that early-long-term potentiation (LTP) in the dentate gyrus can be reinforced into late LTP by stimulation of the basolateral nucleus of the amygdala [Frey et al., submitted for publication]. The pathways and mechanisms for such interactions are unclear, considering that no direct projection from the amygdala to the dentate gyrus is known. To ascertain the possible mediation of the septo-hippocampal projection we have transected the fimbria-fornix (FF) fiber system in young adult (2 months) male rats. The electrophysiological evaluation a week later showed that the lesion does not modify the effects of pre-stimulation of the basolateral amygdala (BLA) on the induction of LTP at the perforant pathway (PP)-granule cells synapses, but impairs its maintenance 1 h later. This suggests that two different pathways might mediate different aspects of the amygdala-hippocampal interactions. One seemed to be anatomically independent from the FF and might influence LTP induction; while the second, probably through the septo-hippocampal fornical projection appeared important for LTP maintenance.

Amygdala↗
PubMed1999

Deletion of the ryanodine receptor type 3 (RyR3) impairs forms of synaptic plasticity and spatial learning.

Deletion of the ryanodine receptor type 3 (RyR3) results in specific changes in hippocampal synaptic plasticity, without affecting hippocampal morphology, basal synaptic transmission or presynaptic function. Robust long-term potentiation (LTP) induced by repeated, strong tetanization in the CA1 region and in the dentate gyrus was unaltered in hippocampal slices in vitro, whereas weak forms of plasticity generated by either a single weak tetanization or depotentiation of a robust LTP were impaired. These distinct physiological deficits were paralleled by a reduced flexibility in re-learning a new target in the water-maze. In contrast, learning performance in the acquisition phase and during probe trial did not differ between the mutants and their wild-type littermates. In the open-field, RyR3(-/-) mice displayed a normal exploration and habituation, but had an increased speed of locomotion and a mild tendency to circular running. The observed physiological and behavioral effects implicate RyR3-mediated Ca(2+) release in the intracellular processes underlying spatial learning and hippocampal synaptic plasticity.

Animals↗