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Biomedical subjects

U Staubli

Publications and source records attributed to U Staubli.

At least 19 recordsLinked to original sources
PubMed1999

The polo-like protein kinases Fnk and Snk associate with a Ca(2+)- and integrin-binding protein and are regulated dynamically with synaptic plasticity.

In order to stabilize changes in synaptic strength, neurons activate a program of gene expression that results in alterations of their molecular composition and structure. Here we demonstrate that Fnk and Snk, two members of the polo family of cell cycle associated kinases, are co-opted by the brain to serve in this program. Stimuli that produce synaptic plasticity, including those that evoke long-term potentiation (LTP), dramatically increase levels of both kinase mRNAs. Induced Fnk and Snk proteins are targeted to the dendrites of activated neurons, suggesting that they mediate phosphorylation of proteins in this compartment. Moreover, a conserved C-terminal domain in these kinases is shown to interact specifically with Cib, a Ca(2+)- and integrin-binding protein. Together, these studies suggest a novel signal transduction mechanism in the stabilization of long-term synaptic plasticity.

Amino Acid Sequence↗
PubMed1999

Pim kinase expression is induced by LTP stimulation and required for the consolidation of enduring LTP.

In animals and several cellular models of synaptic plasticity, long-lasting changes in synaptic strength are dependent on gene transcription and translation. Here we demonstrate that Pim-1, a serine/threonine kinase closely related to Pim-2 and Pim-3, is induced in hippocampus in response to stimuli that evoke long-term potentiation (LTP). Mice deficient for Pim-1 show normal synaptic transmission and short-term plasticity. However, they fail to consolidate enduring LTP even though Pim-2 and Pim-3 are constitutively expressed in the hippocampus and Pim-3 expression is similarly induced by synaptic activity. Thus, expression of Pim-1 is required for LTP. Its level of expression and, consequently, its capacity to phosphorylate target proteins in dendritic and nuclear compartments of stimulated neurons might be a determining factor for the establishment of long-lasting changes in synaptic strength.

Animals↗
PubMed1997

Studies on long-term depression in area CA1 of the anesthetized and freely moving rat.

Homosynaptic long-term depression (LTD) is reported to occur in field CA1 of hippocampal slices collected from immature brains. Because the effect has been postulated to be a memory storage mechanism, it is of interest to test for its presence in adult, awake animals. Unfortunately, not only has hippocampal LTD proved difficult to obtain reliably in vivo, but the few successful studies vary with respect to protocols and evidence that the depression is input-specific. The present study tested for input-specific (homosynaptic) LTD in field CA1 after application of various stimulation protocols to the Schaffer collateral/commissural projections in freely moving, adult rats. The results indicate that although low-frequency trains do induce decrements in synaptic transmission lasting for hours to several days, the success rate of eliciting input-specific LTD in the awake rat is very modest compared with the ease with which stable potentiation is obtained in the same synapses. Moreover, it is questionable that the effective protocols represent patterns of activity likely to occur during behavior. The stronger the afferent activation during low-frequency stimulation, the greater was the probability of eliciting LTD accompanied by persistent heterosynaptic depression. Clear evidence for the occurrence of LTD, irrespective of stimulation protocol and current intensity, could not be obtained in rats under barbiturate anesthesia. In all, the results do not accord with the suggestion that LTD occurs routinely in the hippocampus in vivo as part of memory encoding.

Anesthesia, General↗
PubMed1997

Arg-Gly-Asp-Ser-selective adhesion and the stabilization of long-term potentiation: pharmacological studies and the characterization of a candidate matrix receptor.

Peptides known to block the extracellular interactions of adhesion receptors belonging to a subclass of the integrin family were tested for their effects on the stabilization of long-term potentiation (LTP) in hippocampal slices. Theta burst stimulation delivered after infusions of Gly-Ala-Val-Ser-Thr-Ala (GAVSTA) resulted in a potentiation effect that decayed steadily over a period of 40 min; LTP elicited in the presence of inactive control peptides remained stable over this time period. GAVSTA had no detectible influence on baseline responses, induction processes, or the initial degree of potentiation. Infusions of integrin antagonists after application of theta bursts also resulted in the occurrence of a decremental form of LTP. Affinity chromatography was then used in an effort to identify targets of the structurally dissimilar integrin blockers that disrupt LTP stabilization. Both integrin antagonists Gly-Arg-Gly-Asp-Ser-Pro and GAVSTA eluted a major species of 55 kDa (synaptegrin-1) from GRGDSP-affinity columns that had been loaded with solubilized synaptic membranes; lesser concentrations of three polypeptides of approximately 20, 27, and 30 kDa were also collected. Synaptegrin-1 was labeled by antibodies to the RGDS-binding integrin alpha5beta1. In addition, the synaptegrin, as well as the 27 kDa, protein was found to copurify with pre- and postsynaptic markers during the isolation of forebrain synaptosomes. These results indicate that a matrix recognition event occurring several minutes after induction of LTP is a necessary step in the stabilization of potentiated synapses; they also identify an integrin-like matrix receptor of 55 kDa that may contribute to this event.

Animals↗
PubMed1997

Effects of 5-HT3 receptor antagonism on hippocampal cellular activity in the freely moving rat.

Recent physiological studies conducted in the hippocampi of freely moving rats have revealed that systemic injections of the selective serotonin-3 (5-HT3) receptor antagonist ondansetron facilitate induction of long-term potentiation (LTP), increase the frequency of the theta electroencephalogram rhythm, and enhance retention of memory in hippocampally dependent tasks. To gain insight into the cellular mechanisms underlying these observations, in the present study we examined the effects of intraperitoneal injections of ondansetron on the firing rate of CA1 interneurons and pyramidal cells in the dorsal hippocampi of freely moving rats. Mean firing rates of a substantial proportion (17 of 27) of isolated neurons were significantly different before and after ondansetron injection (500 and 1,000 micrograms/kg). Of the interneurons that exhibited an effect, all (11 of 11) significantly decreased their mean firing rate, with an average change of -22.4 +/- 3.9% (mean +/- SE) across cells. Eighty-three percent (5 of 6) of pyramidal cells showing a change in mean firing rate displayed a significant increase in activity, with an average change of 56.3 +/- 25.6% across cells. Ondansetron (1.0 mg/kg ip) had no detectable effect on spontaneous behavioral activity as measured by line crossings and rearings in an open-field apparatus. The present results show that pharmacological blockade of 5-HT3 receptors causes a reduction in firing activity of a subset of CA1 hippocampal interneurons, with concomitant increases in the firing rate of pyramidal cells. These changes may be directly related to the ondansetron-induced enhancement of LTP induction and memory formation observed in previous studies.

Animals↗
PubMed1994

Serotonin controls the magnitude of LTP induced by theta bursts via an action on NMDA-receptor-mediated responses.

The present studies examined the inhibitory effects of serotonin (5-HT) on LTP in the context of the theta burst stimulation paradigm and its known relationship to the induction chemistries of LTP. Comparisons were made between the effects of various dosages of 5-HT on: (i) the extent to which the second member of a pair of theta bursts was facilitated over the first member of the pair; and (ii) the degree of LTP produced by the paired bursts. Both LTP and burst facilitation were affected in a graded manner by the drug: at high concentrations LTP was completely blocked and burst enhancement was minimal, at lower dosages LTP stabilized at a reduced level while burst responses showed substantial but still impaired facilitation. The competitive antagonist AP-5 was then used to test if 5-HT blocked the NMDA receptor mediated synaptic currents which normally occur during the facilitated burst responses. AP-5 had no effect on the size of burst responses in slices pre-treated with 5-HT indicating that serotonin suppressed the activation of the NMDA receptors by theta stimulation. Serotonin depressed the facilitation of burst responses in slices pre-treated with AP-5 indicating that it also reduces the enhanced AMPA receptor mediated currents that occur during theta pattern stimulation. These results are discussed in terms of the known effects of serotonin on hippocampal physiology and how these might interact with the machinery whereby theta stimulation activates NMDA receptor mediated currents.

2-Amino-5-phosphonovalerate↗
PubMed1994

Facilitation of glutamate receptors enhances memory.

A benzamide drug that crosses the blood-brain barrier and facilitates DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated synaptic responses was tested for its effects on memory in three behavioral tasks. The compound reversibly increased the amplitude and prolonged the duration of field excitatory postsynaptic potentials in hippocampal slices and produced comparable effects in the dentgate gyrus in situ after intraperitoneal injections. Rats injected with the drug 30 min prior to being given a suboptimal number of training trials in a two-odor discrimination task were more likely than controls to select the correct odor in a retention test carried out 96 hr later. Evidence for improved memory was also obtained in a water maze task in which rats were given only four trials to find a submerged platform in the presence of spatial cues; animals injected with the drug 30 min before the training session were significantly faster than vehicle-injected controls in returning to the platform location when tested 24 hr after training. Finally, the drug produced positive effects in a radial maze test of short-term memory. Well trained rats were allowed to retrieve rewards from four arms of an eight-arm maze and then tested for reentry errors 8 hr later. The number of such errors was substantially reduced on days in which the animals were injected with the drug before initial learning. These results indicate that a drug that facilitates glutamatergic transmission enhances the encoding of memory across tasks involving different sensory cues and performance requirements. This may reflect an action on the cellular mechanisms responsible for producing synaptic changes since facilitation of AMPA receptors promotes the induction of the long-term potentiation effect.

Animals↗
PubMed1993

A drug that facilitates glutamatergic transmission reduces exploratory activity and improves performance in a learning-dependent task.

A recently developed benzamide compound which facilitates glutamate receptor-mediated synaptic responses was used to test behavioral consequences of enhanced glutamatergic transmission. The drug was found to depress exploratory activity by rats in a novel environment. At a dose below threshold for causing such effects, drug-treated and control rats exhibited no evident behavioral differences during the acquisition phase of a radial maze experiment. Yet, when tested 2.5 h later, experimental animals were more likely than controls to choose maze arms that had not been entered during the acquisition session, suggesting that the drug enhanced retention of information about prior choices and the maze environment.

Animals↗
PubMed1992

Receptor changes and LTP: an analysis using aniracetam, a drug that reversibly modifies glutamate (AMPA) receptors.

The hypothesis that long-term potentiation (LTP) involves receptor modifications was tested with aniracetam, a nootropic drug that selectively increases currents mediated by the AMPA subclass of glutamate receptors. Aniracetam had different effects on the waveform of synaptic potentials in hippocampus before and after induction of LTP: (1) the drug caused a slight reduction (or delay) of the initial segment of the response after LTP; and (2) the facilitatory effects of aniracetam occurred at a later time point in the response after LTP than before. The interactions between LTP and aniracetam were still present when synaptic responses were greatly reduced by partial blockade of postsynaptic receptors and were not reproduced by increasing release or the number of stimulated synapses. A mathematical treatment of synaptic currents produced the following results: (1) if aniracetam facilitates AMPA receptor currents simply by reducing desensitization, then its complex interaction with LTP emerges when potentiation changes the kinetic and conductance properties of receptor channels; (2) if aniracetam also significantly increases conductance, then the experimental data can be reproduced by modeling LTP as an increase in channel conductance alone.

Animals↗
PubMed1992

A peculiar form of potentiation in mossy fiber synapses.

This chapter is concerned with the unexpected finding that the hippocampus contains two qualitatively different forms of long-lasting potentiation. High-frequency stimulation of the mossy fiber input to CA3 produces an increase in the size of evoked excitatory postsynaptic potentials (EPSPs) that in many respects resembles the long-term potentiation (LTP) effect in CA1. However, work by Harris and Cotman and by Zalutsky and Nicoll showed that mossy fiber potentiation is not induced by the same processes that trigger LTP. Experiments by this author have revealed that the two phenomena are based on different expression mechanisms: mossy fiber potentiation is associated with a decrease in paired-pulse facilitation indicating that its expression involves presynaptic changes; and LTP in the Schaffer-commisural projections does not affect paired-pulse facilitation or any of several other manipulations that increase release, suggesting that it is expressed by postsynaptic modifications. Direct evidence for the above conclusions has been obtained using aniracetam, a drug which selectively enhances currents mediated by the AMPA (quisqualate) receptors. As expected from its action on receptors, field EPSPs are increased by aniracetam; this effect is proportionally smaller following induction of LTP, but not after mossy fiber potentiation. These findings support the hypothesis that LTP reflects a change in the properties of AMPA receptors. In summary, the effects of presynaptic treatments are reduced by mossy fiber potentiation but not by LTP while a postsynaptic treatment is affected by LTP but not by mossy fiber potentiation. The above results point to the conclusion that mossy fiber potentiation is unlike LTP both in induction and expression mechanisms and thus is a wholly different form of synaptic plasticity.

Animals↗
PubMed1991

Selective effects of aniracetam across receptor types and forms of synaptic facilitation in hippocampus.

Aniracetam reversibly increased synaptic responses mediated by the AMPA but not the NMDA subclass of glutamate receptors in hippocampus and was considerably more potent than structurally similar nootropics. The drug had greater effects on field excitatory postsynaptic potentials (EPSPs) in the dentate gyrus and CA1 region than it did in the CA3 region, suggesting that it differentiates between variants of the AMPA receptor. Ligand binding to glutamate receptors in synaptosomal membrane fractions was minimally changed by aniracetam. Finally, the percent facilitation produced by aniracetam in the CA1 region was not reduced by any of three treatments (4-aminopyridine, changes in extracellular calcium concentrations, paired-pulse stimulation) that affect release but, in accord with a previous report, was substantially decreased by long-term potentiation. These results support the conclusion that aniracetam selectively increases the conductance of a subgroup of synaptic AMPA receptors in hippocampus and suggest that receptor changes underlie the expression of long-term potentiation.

4-Aminopyridine↗
PubMed1991

Hippocampus and olfactory discrimination learning: effects of entorhinal cortex lesions on olfactory learning and memory in a successive-cue, go-no-go task.

Three experiments assessed the effect of entorhinal cortex lesions on olfactory learning and memory using a successive-cue olfactory discrimination paradigm. In contrast to the results of other studies that used a simultaneous-cue paradigm, lesions of the entorhinal cortex facilitated rats' acquisition of individual odor discrimination problems, with no impairment in memory for the individual odors across both short (24-hr) and long (65-day) retention intervals and despite limited training. When considered together with previous observations of facilitation or impairment in learning after damage to the hippocampal system, the present data suggest that the hippocampus is preferentially involved in encoding relations among multiple stimuli. By this account, facilitation of performance is due to an interaction between hippocampal system dysfunction and task conditions that hinder direct comparisons among cues.

Animals↗
PubMed1991

Evidence that matrix recognition contributes to stabilization but not induction of LTP.

Slices of hippocampus were incubated with Arg-Gly-Asp (RGD) peptides known to block members of the integrin class of matrix receptors. Though the peptides caused no detectable difference in the amount of long-term potentiation (LTP) expressed in the CA1 field 1-2 min after induction with high frequency stimulation, they did produce a reversible, dose dependent decay of LTP over a period of 40 min. This effect was not obtained with various non-RGD control peptides. These results suggest that stabilization of LTP requires adhesive interactions via specific matrix recognition sites, whereas induction and expression do not.

Amino Acid Sequence↗
PubMed1990

Stable depression of potentiated synaptic responses in the hippocampus with 1-5 Hz stimulation.

Adult rats with two chronic stimulating electrodes in the Schaffer collateral/commissural system of the hippocampus and one recording electrode in the stratum radiatum (apical dendrites) of field CA1 were administered high-frequency stimulation (10 brief bursts at theta frequency) to produce long-term potentiation (LTP). 'Low frequency' stimulation (100 pulses at 1 Hz alone or followed by 250 pulses at 5 Hz) delivered 5-15 min later had no effect on LTP in 18% of the rats, caused a transient reversal in 18% of the group, but produced an apparent reversal of LTP for the remainder of a 1 h test session in 64% of the animals. LTP did not recover in animals tested 24 h later, at which point a second episode of high-frequency stimulation but without subsequent low-frequency stimulation was administered. This produced an LTP effect that persisted for a 1 h test session in 94% of the cases and that was still present in 86% of the animals tested 24 h later. Low-frequency stimulation applied prior to induction of LTP had no lasting effects on evoked responses not did it affect responses to a control stimulating electrode in those cases in which it reversed LTP. Possible implications of these results for hypotheses concerning the substrates of LTP and mechanisms of forgetting are discussed.

Action Potentials↗