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Biomedical subjects

M Krug

Publications and source records attributed to M Krug.

At least 37 records · Page 2Linked to original sources
PubMed1999

Effects of piracetam on pentylenetetrazol-kindling development, hippocampal potentiation phenomena and kindling-induced learning deficit.

Kindling is a generally accepted model for studying epilepsy development in the context of overexpression of processes of neuronal plasticity. In previous studies we have shown that establishment of kindling by repeated application of subconvulsive doses of pentylenetetrazol (PTZ) also led to marked changes in hippocampal excitability and an impairment in learning behaviour. With the intention of further investigating the relationship between kindling development, kindling-induced changes in excitability and learning deficits, rats were chemically kindled under pretreatment with the nootropic drug piracetam. Furthermore, we tested acute piracetam effects on developed kindling seizures, the learning deficit and potentiation effects. At the investigated dose piracetam did not influence the kindling development. The kindling-induced potentiation of hippocampal field potentials was significantly diminished in piracetam-pretreated rats. Piracetam acutely injected completely antagonized this potentiation effect. Piracetam brought about a significant improvement in impaired learning performance in rats pretreated during kindling induction and acutely injected before the learning experiment, respectively. Possible correlations between the suppressing of the kindling related potentiation in hippocampal structures by piracetam and its beneficial effect on learning impairment are discussed as antagonizing overexpression of potentiation in the course of kindling.

Animals↗
PubMed1999

Effects of nicardipine, an antagonist of L-type voltage-dependent calcium channels, on kindling development, kindling-induced learning deficits and hippocampal potentiation phenomena.

Kindling is considered to be a useful experimental model for investigating drug effects on the convulsive component of epilepsy and related alterations at the behavioural level. It was demonstrated that pentylenetetrazol (PTZ)-kindled rats show diminished learning performance in shuttle-box training. We used this model to study the influence of nicardipine, an antagonist of L-type voltage-dependent calcium channels, on kindling seizure development as well as related learning impairments. Additionally, we tested the influence of nicardipine on kindling-induced potentiation, a special form of long-term enhancement of evoked potentials in the dentate gyrus after kindling. Therefore, monosynaptic evoked field potentials in the dentate area upon test stimuli to the perforant pathway were recorded in freely moving kindled and control rats at different times after injection of PTZ. The results indicate that the blockade of L-type voltage-dependent Ca2+-channels during the kindling procedure attenuates PTZ-kindling, antagonizes a kindling-induced learning deficit in an active avoidance test and decreases a novel form of kindling-related potentiation, the long-lasting amplitude enhancement of the monosynaptic evoked field potential in the dentate gyrus after injection of a small test dose of PTZ. This potentiation can also be prevented in kindled animals by nicardipine injection in an acute experiment.

Animals↗
PubMed1999

Glycosylation of proteins during a critical time window is necessary for the maintenance of long-term potentiation in the hippocampal CA1 region.

This paper focuses on the role of glycoproteins in activity-dependent synaptic plasticity. The effect of the different inhibitors of protein glycosylation, Tunicamycin, Brefeldin A and Swainsonine, on long-term potentiation was studied in the CA1 region of rat hippocampal slices. Bath application of the inhibitors 60 min before and during tetanization did not interfere with the induction of long-term potentiation of the field excitatory postsynaptic potential. However, the potentiation in inhibitor-treated slices decreased to baseline levels during 90-180 min. Significant differences in the potentiation in non-treated slices were detectable 80 min (Tunicamycin), 60 min (Brefeldin A) and 75 min (Swainsonine) after tetanization, thus indicating the prevention of long-term potentiation maintenance. The application of Swainsonine 120 and 240 min after tetanization did not influence the potentiated field excitatory postsynaptic potential. These data demonstrate the need for undisturbed glycoprotein processing in a time window around long-term potentiation induction to maintain later phases of long-term potentiation and essential functional implications of protein glycosylation in mechanisms underlying synaptic plasticity.

Animals↗
PubMed1998

Increase in proportion of hippocampal spine synapses expressing neural cell adhesion molecule NCAM180 following long-term potentiation.

Neural recognition molecules such as the neural cell adhesion molecule (NCAM) have been implicated in synaptic plasticity, including long-term potentiation (LTP), sensitization, and learning and memory. The major isoform of NCAM carrying the longest cytoplasmic domain of all NCAM isoforms (NCAM180) is predominantly localized in postsynaptic membranes and postsynaptic densities of hippocampal neurons, with only a proportion of synapses carrying detectable levels of NCAM180. To investigate whether this differential expression of NCAM180 may correlate with distinct states of synaptic activity, LTP was induced by high-frequency stimulation of the perforant path and the percentage of NCAM180 immunopositive spine synapses determined in the outer third of the dentate molecular layer of the dentate gyrus by immunoelectron microscopy. Twenty-four hours following induction of LTP by high-frequency stimulation, the percentage of spine synapses expressing NCAM180 increases from 37% (passive control) to 70%. This increase was inhibited by the noncompetitive N-methyl-D-aspartate receptor antagonist MK801. Following repeated LTP induction at 10 consecutive days with one tetanization each day, 60% of all spine synapses were NCAM180 immunoreactive. Compared to passive control animals, the percentage of NCAM180 expressing synapses in low-frequency stimulated animals decreased from 37% to 28%. Spine synapses in the inner part of the dentate molecular layer not contacted by the afferents of the perforant path did not change the percentage of NCAM180-expressing synapses. The results obtained by the postembedding immunogold staining technique confirmed the difference in NCAM180 expression of spine synapses between passive control and potentiated animals. These observations suggest a role for NCAM180 in synaptic remodeling accompanying LTP.

Animals↗
PubMed1998

Effects of anticonvulsive drugs on pentylenetetrazol kindling and long-term potentiation in freely moving rats.

Drugs with anticonvulsive properties and different mechanisms of action were compared for their influence on long-term potentiation and pentylenetetrazol kindling in freely moving animals. Rats were chronically implanted with a stimulation electrode in the angular bundle and a recording electrode in the dentate gyrus. Field potentials in the dentate gyrus were elicited and long-term potentiation was induced by stimulation of the perforant pathway. The clinically used drugs or the potentially anticonvulsive drugs, diphenylhydantoin (50 mg/kg), diazepam (0.5 mg/kg), pentobarbital (10 mg/kg), dizocilpine (MK 801, 0.2 mg/kg) and CGP 43487 (2-amino-4-methyl-5-phosphono-3-pentenoic acid-carboxyethylester, 10 mg/kg), were injected before tetanization. In behavioural experiments pentylenetetrazol kindling was performed with pretreatment with the substances in dosages indicated above (except MK 801, 0.3 mg/kg). Field potentials recorded in the interval between drug administration and tetanization were influenced only by diphenylhydantoin which enhanced the population spike amplitude to 128% of control values. However, the substances showed different effects on long-term potentiation. MK 801, CGP 43487 and pentobarbital depressed potentiation; diazepam was without effect. Diphenylhydantoin had a minor influence on induction but significantly impaired maintenance of long-term potentiation. Furthermore, MK 801, CGP 43487, diazepam and pentobarbital differentially depressed kindling whereas phenytoin only slightly influenced it. The consequences as to hypothetical common cellular mechanisms for kindling development and long-term potentiation are discussed.

Animals↗
PubMed1997

Design of a multiple slice interface chamber and application for resolving the temporal pattern of CREB phosphorylation in hippocampal long-term potentiation.

We describe an improved method for the investigation of time-dependent intracellular events giving rise to long-lasting changes in synaptic efficacy. A new interface chamber for the simultaneous superfusion of approximately 30 rat hippocampal slices was designed. The slice chamber contains an upper and a lower medium reservoir connected by a grooved incubation platform which is mounted at an angle of 7 degrees on a thermoregulation unit. Surface slices placed in the chamber are perfused with oxygenated medium at a rate of 1 ml/min and are maintained synaptically viable for at least 6 h. At different time points after induction of long-term potentiation by stimulation of the Schaffer collateral pathway, slices were either fixed in Zamboni's fixative or the CA1 region was excised and lysed in boiling SDS-sample buffer. Fixed 400 microm hippocampal slices were cut into 30 microm sections and immunocytochemically stained with an anti-serine 133 phosphorylated cAMP-responsive element binding protein (pCREB) antibody. Binding of primary antibody was detected with the avidin-biotinylated peroxidase complex method and enhanced using peroxidase-catalyzed deposition of biotinylated tyramine. Staining was visualized with streptavidin-cyanine 3.18 and observed under a confocal laser scanning microscope. CA1 lysates were electrophoresed and subjected to Western blot analysis. Both pCREB immunocytochemical staining and Western blotting showed that CREB is rapidly and transiently phosphorylated after induction of long-term potentiation. pCREB levels peaked within 30 min and declined back to control after 60 min. Immunocytochemistry also showed that pCREB was localized to the nuclei of CA1 pyramidal cells near the tetanization site.

Animals↗
PubMed1997

Dopamine D1-deficient mutant mice do not express the late phase of hippocampal long-term potentiation.

The possible involvement of the dopamine D1 receptor subtype in mechanisms of long-term potentiation (LTP) of the Schaffer collateral-commissural input of CA1 neurones was investigated using D1-deficient mutant mice. In transversal hippocampus slices from mice lacking the D1 receptor a normal post-tetanic and short-term potentiation could be induced after applying a triple 100 Hz tetanization. However, the potentiated fEPSP in the mutant mice declined to control value about 140 min following tetanization, whereas in the wild type mice a normal, non-decremental LTP was observed. These data support the idea that besides the glutamatergic system, the synergistic activation of dopaminergic synapses is necessary for LTP maintenance.

Animals↗
PubMed1997

Strain differences in pentylenetetrazol-kindling development and subsequent potentiation effects.

Rats from two different strains, i.e. Wistar rats and Lister hooded rats, were investigated for their ability to acquire the kindling syndrome. After having received 13 kindling stimulations (injection of pentylenetetrazol), the animals were tested for subsequent alterations in induction and maintenance of hippocampal long-term potentiation (LTP) and, moreover in glutamate binding. It was found that rats from both strains did not differ in the response to the initial injection of pentylenetetrazol (PTZ) and the amplitude of the population spike. This suggests that some aspects of basic central excitability are equivalent. Wistar rats acquired the kindling syndrome rapidly whereas seizure outcome was poor in Lister rats. As regards hippocampal LTP, the population spike was only dramatically increased in Wistar rats after kindling completion. Glutamate binding was not altered in animals from the Lister strain. The results suggest that changes in glutamate binding and the increase in the population spike are characteristic consequences of kindling.

Animals↗
PubMed1997

Pentylenetetrazol kindling changes the ability to induce potentiation phenomena in the hippocampal CA1 region.

The present study describes changes of response enhancement of hippocampal field potentials in slices of kindled rats using different methods to induce long-lasting potentiation. Eight-week-old male Wistar rats were subjected to pentylenetetrazol (PTZ) kindling induced by intraperitoneal injection of 45 mg/kg once every 48 h until the occurrence of seizure stages 4-5. Eight to 12 days after the last kindling session, transverse hippocampus slices were prepared and maintained in an artificial medium. Evoked-field potentials were recorded in the CA1 region upon stimulation of the Schaffer collaterals. Potentiation was induced: 1. By moderate tetanic stimulation of the Schaffer collaterals, 2. by changing the perfusion medium to 0-magnesium for 30 min, and 3. by changing the medium to 4 mM Ca2+ for 7 min. In slices from kindled rats, long-term potentiation (LTP) after tetanic stimulation and increase of the evoked potential by 0-magnesium were significantly enhanced in comparison to slices from sham-kindled rats. However, Ca(2+)-induced LTP could not be induced in slices from kindled rats. The results support the assumption that PTZ kindling also induces lasting changes in the responsiveness of hippocampal structures, expressed as an enhanced ability to induce potentiation. An alteration of N-methyl-D-aspartate (NMDA) receptor-coupled processes can be assumed. The inability to induce Ca(2+)-induced LTP points to more complex effects of PTZ, perhaps also on nonNMDA coupled ionic channels.

Animals↗
PubMed1997

Inhibition by compactin demonstrates a requirement of isoprenoid metabolism for long-term potentiation in rat hippocampal slices.

Hippocampal long-term potentiation of synaptic transmission is the primary experimental model of learning and memory in the vertebrate brain. However, the detailed intracellular mechanisms giving rise to this persistent increase in synaptic efficacy remain incompletely understood. Mevalonic acid constitutes the basic precursor not only for cholesterol, dolichol and ubichinone but also for farnesyl-pyrophosphate and geranylgeranylpyrophosphate, which are required for post-translational modification of proteins. We have used the specific 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, compactin, to examine the role of isoprenoid metabolism for long-term potentiation in rat hippocampal slices. Compactin was applied at a concentration of 25 microM for 70 min before and during tetanization and the orthodromic population spike amplitude and field excitatory postsynaptic potentials were recorded from CA1 pyramidal cells. Compactin had no effect on the initial tetanization. However, compactin-treated slices were not able to maintain long-term potentiation for more than 60 min and population spike as well as field excitatory postsynaptic potentiation returned to basal levels after 120 min. When the slices were retetanized after 180 min, an almost full potentiation of the population spike and an only partial potentiation of the field excitatory postsynaptic potentials were observed. These results suggest an essential role of isoprenoid intermediates for maintenance of hippocampal long-term potentiation.

Animals↗
PubMed1996

Fucose and fucosyllactose enhance in-vitro hippocampal long-term potentiation.

Bath application of L-fucose and 2-fucosyllactose (2FI) increases the potentiation of the population spike amplitude (POP-spike) and the field excitatory postsynaptic potential (fEPSP) after tetanization of the Schaffer collaterals of the rat hippocampus. The ineffective isomers D-fucose and 3-fucosyllactose (3-FI) have no such effect. Since not only the maintenance of long-term potentiation LTP is influenced but also its induction is drastically improved, an effect of the sugars via the formation of glycoproteins but also via different actions on induction mechanisms is discussed.

Animals↗
PubMed1996

Influence of actinomycin D, a RNA synthesis inhibitor, on long-term potentiation in rat hippocampal neurons in vivo and in vitro.

1. Hippocampal long-term potentiation (LTP) may serve as an elementary process underlying certain forms of learning and memory in vertebrates. As is the case with behavioural memory, hippocampal LTP in the rat CA1 region and in the dentate gyrus occurs in stages, which can be separated by an inhibitor of RNA synthesis. 2. Experiments have been performed in two brain regions, in the hippocampal CA1 region in vitro and in the dentate gyrus in vivo. 3. Maintenance of hippocampal LTP in the CA1 region in vitro was influenced by the RNA synthesis inhibitor actinomycin D from 4 h onwards. 4. The effect of actinomycin D on the time course of the population spike potentiation was more pronounced than the effect on the time course of the EPSP component, suggesting different mechanisms for the two forms of potentiation. 5. Intrahippocampal and intracerebroventricular injection of actinomycin D into rats prevented a late stage of LTP in the dentate gyrus in vivo measured as the population spike amplitude. 6. Since actinomycin D was only effective in influencing the maintenance of LTP when applied before tetanization, the requirement for transcription during LTP may have a critical time window. 7. Actinomycin D influenced the maintenance of LTP specifically, since the drug did not alter any potentials in control experiments after its removal or when it was administered shortly after tetanization. A second, structurally different RNA synthesis inhibitor, 5,6-dichloro-1-beta-D-ribofuranosyl benzimidazole, mimicked the effect of actinomycin D in vitro.

Animals↗
PubMed1996

The comparison of geometric and electronic properties of molecular surfaces by neural networks: application to the analysis of corticosteroid-binding globulin activity of steroids.

It is shown how a self-organizing neural network such as the one introduced by Kohonen can be used to analyze features of molecular surfaces, such as shape and the molecular electrostatic potential. On the one hand, two-dimensional maps of molecular surface properties can be generated and used for the comparison of a set of molecules. On the other hand, the surface geometry of one molecule can be stored in a network and this network can be used as a template for the analysis of the shape of various other molecules. The application of these techniques to a series of steroids exhibiting a range of binding activities to the corticosteroid-binding globulin receptor allows one to pinpoint the essential features necessary for biological activity.

Drug Design↗
PubMed1996

Potentiation effects in the dentate gyrus of pentylenetetrazol-kindled rats.

The study examines changes in the function of perforant pathway dentate granule cell synapses after pentylenetetrazol (PTZ) kindling. Field potentials evoked in the dentate area by test stimuli to the perforant pathway were recorded in freely moving rats at different times after injection of PTZ. In fully kindled animals, but not in sham-kindled controls, subconvulsive test doses of PTZ induced long-lasting potentiation of the population spike. Also, potentiation was not induced in naive controls injected with equieffective doses of the convulsant. The slope function of the field EPSP was depressed 90-120 min after PTZ administration, in both kindled and control animals, indicating that this was an effect of acute-injected PTZ. Later on, only in kindled animals that showed seizure stages 4 or 5 did it increase in parallel with the population spike potentiation. Finally, when compared to controls the kindled animals showed a greater pop spike potentiation induced by moderate tetanization of the perforant pathway. The model offers the possibility of differentiating between acute effects of the convulsant drug and kindling-related changes in neuronal plasticity.

Animals↗
PubMed1996

Proteus syndrome associated with a sacrococcygeal teratoma; a rare combination.

We report on an 5-year-old boy with a Proteus syndrome known since his second year of life. Hidden in a lipomatous tumor we excised a sacrococcygeal teratoma which must have been present since birth. This is the first case, out of about 50 published Proteus cases, of a patient with Proteus syndrome and sacrococcygeal teratoma.

Bone Neoplasms↗
PubMed1995

NMDA/R1-antisense oligonucleotide influences the early stage of long-term potentiation in the CA1-region of rat hippocampus.

We have studied the role of the N-methyl-D-aspartate (NMDA)/R1 receptor subunit in the mechanism of long-term potentiation (LTP) using an antisense-oligodeoxynucleotide strategy. Antisense-oligodeoxynucleotide (aDON; 10 nmol) or sense-oligodeoxynucleotide (sDON) were applied into the right ventricle of 7 week old male Wistar rats every 12 h for 3 days. Thereafter, in hippocampal slices extracellular field potential recordings were made from the CA1 region. LTP was induced by tetanization of the Schaffer collaterals. In slices of rats pretreated with aDON the initial potentiation of the population spike (POP-spike) was significantly smaller than in those from saline controls and naive animals. The impairment of potentiation lasted for about 50 min posttetanus. However, the potentiation of the field excitatory postsynaptic potentials (fEPSPs) was significantly influenced for 15 min. In slices of rats pretreated with sDON only a small, insignificant difference in POP-spike and fEPSP potentiation was seen compared to saline controls. In the group pretreated with aDON the specific binding of [3H]glutamate to the NMDA-receptor subtype of hippocampal membranes was reduced to about 63% in comparison with the group treated with sDON. These results indicate that DONs reached the target region when applied intraventricularly and were able to suppress the translation of mRNA of the NMDA/R1 receptor subunit. They further support the assumption of the essential role of the NMDA/R1 receptor subunit in the induction of LTP.

Animals↗
PubMed1995

Somatodendritic expression of an immediate early gene is regulated by synaptic activity.

Trans-synaptic activation of gene expression is linked to long-term plastic adaptations in the nervous system. To examine the molecular program induced by synaptic activity, we have employed molecular cloning techniques to identify an immediate early gene that is rapidly induced in the brain. We here report the entire nucleotide sequence of the cDNA, which encodes an open reading frame of 396 amino acids. Within the hippocampus, constitutive expression was low. Basal levels of expression in the cortex were high but can be markedly reduced by blockade of N-methyl-D-aspartate receptors. By contrast, synaptic activity induced by convulsive seizures increased mRNA levels in neurons of the cortex and hippocampus. High-frequency stimulation of the perforant path resulted in long-term potentiation and a spatially confined dramatic increase in the level of mRNA in the granule cells of the ipsilateral dentate gyrus. Transcripts were localized to the soma and to the dendrites of the granule cells. The dendritic localization of the transcripts offers the potential for local synthesis of the protein at activated postsynaptic sites and may underlie synapse-specific modifications during long-term plastic events.

Amino Acid Sequence↗