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G Kostopoulos

Publications and source records attributed to G Kostopoulos.

At least 19 recordsLinked to original sources
PubMed1995

Simulation study for the transition from spindles to spike and wave epileptogenesis.

A mathematical model is presented, based on existing anatomical and physiological data, which simulates the behaviour of representative types of cortical cells. It is used to test whether a set of synaptic connections of these cells exists, which, paced by the same rhythmical thalamic input, could produce spindles under normal conditions and spike and wave discharges (SW) under conditions of cortical hyperexcitability. This is possible if the interneurons do not provide recurrent excitatory or inhibitory input on themselves, if the thalamic afferents contact the cortical projecting pyramidal cells through local excitatory neurons, and if the inhibitory interneurons receive input only from the pyramidal cells. The results suggest that an increase of all cortical synaptic actions (both excitatory and inhibitory) is sufficient for the transition from spindles to the first stages in the development of SW discharges in the cortex, whereas the thalamus can be driven to the SW characteristic frequency at the immediate next stages.

Cerebral Cortex↗
PubMed1993

Upregulation of A1 adenosine receptors in human temporal lobe epilepsy: a quantitative autoradiographic study.

A significant increase of A1 adenosine receptor binding (48% increase of mean) was detected in human neocortex obtained from patients suffering from temporal lobe epilepsy as compared to control neocortex from non-epileptic patients. Such increase was equally distributed in the six cortical layers and reached similar levels in each of the five specimens tested independently of age, sex and pharmacological treatment of the patient. Since adenosine exerts a depressant effect on neocortical neurons in slices obtained from epileptic patients, this upregulation of A1 receptor binding may constitute a protective mechanism against subsequent seizures, which is exerted by elevating the depressant response of the brain to endogenous adenosine.

Adenosine↗
PubMed1993

Effect of pentylentetrazol-induced seizures on A1 adenosine receptor regional density in the mouse brain: a quantitative autoradiographic study.

Adenosine has been shown to be a major regulator of neuronal activity in convulsive disorders, exerting its anticonvulsant effect through central A1 adenosine receptors. The aim of the present study was to investigate the effect of generalized tonic-clonic seizures induced by pentylentetrazol on regional changes in A1 adenosine receptor density and distribution in the mouse brain by in vitro quantitative autoradiography. As radioligand the specific agonist of A1 receptors [3H]cyclohexyladenosine was used. After two consecutive (once daily) pentylentetrazol-induced convulsions a widespread upregulation of A1 receptor density was detected with a marked enhancement in structures that mediate seizure activity like hippocampus, mamillary bodies, septum, substantia nigra, thalamic nuclei and cerebral cortices. On the contrary, in basal ganglia a significant downregulation of A1 receptors was observed. These results indicate that: (i) the observed increases or decreases in A1 receptor density are organized in selective anatomical structures related to seizure development rather than uniform in the brain; and (ii) since the upregulation of A1 receptors is sufficient to enhance the physiological depressive response of adenosine, the overall evoked increases seen here may lead to a stronger inhibitory tone and accordingly to a more efficient anticonvulsant effect of endogenous adenosine.

Adenosine↗
PubMed1991

Changes in seizure latency correlate with alterations in A1 adenosine receptor binding during daily repeated pentylentetrazol-induced convulsions in different mouse brain areas.

The seizure latency changed during daily pentylentetrazol (PTZ) induced convulsions showing an increase between days 2 and 4, a rapid decrease between days 5 and 10 and a slight increase again between days 11 and 14. At the respective timepoints, [3H]CHA binding, in cortex and cerebellum of PTZ treated animals followed exactly the same pattern, suggesting that the alterations in A1 receptors in these areas may partly determine the PTZ seizure latency curve. On the contrary, the changes of [3H]CHA binding in hippocampus (sustained increase) and striatum (sustained decrease) didn't follow the latency curve pattern. These results suggest that changes in A1 receptor density in specific brain areas may be involved in the modulation of seizure susceptibility.

Adenosine↗
PubMed1991

Long-term increase in excitability induced by Mg(2+)-free medium in the absence of afferent stimulation in CA1 area of mouse hippocampal slices.

Omission of Mg ions from the perfusion fluid of hippocampal slices unblocks the N-methyl-D-aspartate (NMDA) type of glutamate receptor/channel, and induces long term enhancement of synaptic responses. In order to test the role of afferent activation in induction of long term potentiation in CA1 area by this process, we switched off stimulation during the time of perfusing the slices with Mg(2+)-free medium (30 min). In addition to a short lasting increase in synaptic activation we observed a long term increase in population spike amplitude in all slices tested (n = 5), which lasted for at least 2 h. This process was antagonized by 50-100 microM DL-2-amino-5-phosphonovalerate, a specific NMDA receptor antagonist (n = 8), but not by isolating CA1-CA3 areas prior to the testing (n = 5). These results suggest that the resting levels of the endogenous excitatory neurotransmitter(s) can induce long term increase in firing probability of CA1 pyramidal cells, when NMDA channels are unblocked, in the absence of afferent stimulation and irrespective of CA3 area prior excitation.

2-Amino-5-phosphonovalerate↗
PubMed1991

A comparison of recurrent inhibition and of paired-pulse facilitation in hippocampal slices from normal and genetically epileptic mice.

Tottering mice exhibit inherited generalized epilepsy of the 'absence' type. In hippocampal slices from these mutant mice studied in vitro, pairing an alvear antidromic stimulus to an orthodromic one revealed a strong recurrent inhibition (RI) of CA1 pyramidal neurons. RI was maximal at 10 ms inter-pulse interval (IPI 70% decrease of population spike, PS) gradually decreasing to 15% at 320 ms IPI. At 10 ms IPI it shifted the input/output curves to the right and decreased maximum PS. In the group of slices from epileptic mice the early part of RI (2.5-60 ms) was indistinguishable from that of normal mice, with respect to both its strength and its liability to activity-dependent decrement induced by a train of antidromic stimuli (8 s, 5 Hz). However, the delayed part (80-320 ms) was slightly stronger in the epileptic group. Also in this group only the train of antidromic pulses caused a significant and lasting decrease in the unconditioned orthodromic PS. Paired-pulse facilitation was equally strong in the 2 groups of slices. It is concluded that mechanisms underlying epileptogenic hyperexcitability in the tottering mutant may not include a failure of inhibition, at least in the CA1 area of the hippocampus. On the contrary some inhibitory mechanisms may be stronger.

Animals↗
PubMed1991

Electrophysiological analysis of human neocortex in vitro: experimental techniques and methodological approaches.

In this review we summarize a number of technical and methodological approaches that have been used in our laboratory to study human brain slices maintained in vitro. The findings obtained in the course of these studies appear to be relevant in establishing the mechanisms that underlie physiological phenomena of the human brain such as synaptic plasticity or responses to neuroactive drugs. Moreover, these data are important for understanding certain fundamental mechanisms of epilepsy. In this respect, however, we caution that the mechanisms that apply to different forms of clinical epilepsy might be difficult to find given the variability present in the pathogenesis of human epilepsy.

Cerebral Cortex↗
PubMed1990

Alterations of A1 adenosine receptors in different mouse brain areas after pentylentetrazol-induced seizures, but not in the epileptic mutant mouse 'tottering'.

Single and repeated Pentylentetrazol (PTZ)-induced convulsions are associated with significant changes of A1 adenosine receptors (detected using the radioligand [3H]cyclohexyladenosine, [3H]CHA) in 4 different brain areas of the mouse, namely cortex, hippocampus, cerebellum and striatum. In hippocampus and cerebellum, a rapid increase in [3H]CHA binding, by 26% and 30% respectively, was observed 1 h after a single PTZ convulsion. In striatum, on the contrary, a significant decrease by 30% in [3H]CHA binding was seen, whereas in cortex no significant change could be detected. After daily repeated PTZ convulsions, a significant increase of A1 receptors by 26% appeared also in cortex, while the changes of A1 receptors observed in the other brain areas after a single PTZ convulsion were maintained in almost the same range. All the alterations observed were due to changes of the total number of A1 receptors (Bmax) without changes in receptor affinity (Kd). A significant increase in the latency of PTZ seizure (time between the PTZ-injection and the beginning of the seizure) was also observed after repeated PTZ-induced convulsions at the time when the changes in A1 adenosine receptors were noted. Considered together, these results provide further evidence for an A1 receptor-mediated modulation of seizure susceptibility and indicate that specific brain areas may play different roles in this modulation. The binding of [3H]CHA to membranes from different cortical and subcortical areas of the epileptic mutant mouse 'tottering' was not different from that in control animals.

Adenosine↗
PubMed1990

An electrophysiological study of the ontogenesis of adenosine receptors in the CA1 area of rat hippocampus.

The depressant effect of adenosine (Ad) was studied electrophysiologically in hippocampal slices from 5-, 10-, 15-, 20-, 30- and 120-day-old rats. Ad (10 microM) depressed the field EPSP in CA1 to the same extent in all age groups. Caffeine (Caf), an Ad receptor antagonist, enhanced and nitrobenzylthioinosine (NBI), an Ad uptake blocker, depressed the field EPSP. Both these effects were, however, less prominent in slices from younger animals, a finding consistent with lower extracellular levels of endogenous Ad in neonatal rats.

Action Potentials↗
PubMed1990

Long-term enhancement of postsynaptic excitability after brief exposure to Mg2(+)-free medium in normal and epileptic mice.

Brief exposure to Mg2(+)-free medium (MFM) enhanced the population response of CA1 neurons to stratum radiatum stimulation in hippocampal slices from normal (+/?) and epileptic tottering (tg/tg) mice. The enhancement was maintained in both groups for at least 2 h following reperfusion with normal medium (NM). Excitability curves obtained from the extracellular records suggest that, while both synaptic activation and postsynaptic excitability are enhanced during MFM perfusion, only the latter enhancement is maintained at significant levels after reperfusion with NM. The long-term increase in postsynaptic excitability was comparable in strength to that produced by long-term potentiation (LTP) inducing tetanic stimuli, was accompanied by an increase in the slope of the population spike/field excitatory postsynaptic potential (PS/fEPSP) curve and did not appear to depend on the induction of epileptiform activity by MFM. Both the short- and the long-term effects of MFM on synaptic activation and postsynaptic excitability were qualitatively similar in normal and epileptic mice and any quantitative differences were not statistically significant. Thus, epileptogenesis in the tottering mutant may not involve a change in the NMDA receptor-mediated control of excitability, at least in the CA1 area of hippocampus.

Action Potentials↗
PubMed1989

Endogenous adenosine can reduce epileptiform activity in the human epileptogenic cortex maintained in vitro.

The effects induced by adenosine and some related compounds upon Mg2+-free epileptogenesis were studied in slices of human epileptogenic neocortex maintained in vitro. Extracellular recordings revealed stimulus-induced and spontaneous epileptiform activity within 1-2 h of perfusion with Mg2+-free medium. A 30-90% decrease of the frequency of occurrence of spontaneous epileptiform discharges was induced by 40-50 microM adenosine while the analog 2-Cl-adenosine exerted a depressant effect (greater than 75% reduction in frequency of occurrence) at 0.3-3 microM. 2-Cl-adenosine also depressed stimulus-induced epileptiform responses and often blocked spontaneous epileptiform activity. Similar effects were seen during bath application of the adenosine uptake inhibitor nitrobenzylthioinosine (10-50 microM) indicating that endogenous adenosine can by itself influence epileptogenicity. Our data demonstrate that in the human epileptogenic neocortex a purinergic mechanism can control Mg2+-free epileptiform activity.

Adenosine↗
PubMed1988

Membrane properties, response to amines and to tetanic stimulation of hippocampal neurons in the genetically epileptic mutant mouse tottering.

The petit-mal seizures of the "tottering" mutant mouse (tg) have been attributed to an exaggerated noradrenergic projection from locus coeruleus to the telencephalon (Noebels 1984). In order to investigate the possible epileptogenic mechanisms involved, we have compared hippocampal slices from epileptic (tg/tg) and phenotypically healthy (tg/+) mice. Resting potentials, action potentials and afterpotentials, membrane impedances and time constants were not significantly different in 11 neurons from each group. Bath application of noradrenaline, isoproterenol and histamine or a transient exposure to Mg++-free medium caused a long lasting increase in extracellularly recorded population spikes induced in CA1 by electrical stimulation of stratum radiatum. Isoproterenol blocked the calcium dependent afterhyperpolarization and accommodation of firing. Tetanization of afferent fibres evoked post-tetanic potentiation and long-term potentiation. All these results are qualitatively similar to those previously described in rats and guinea pigs and have revealed no significant difference between tg/tg and tg/+ mice.

Action Potentials↗
PubMed1987

Absence of modification in GABA and benzodiazepine binding and in choline acetyltransferase activity in brain areas of the epileptic mutant mouse tottering.

1. In the tottering mutant mouse, which suffers from epilepsy and cerebellar ataxia, we examined whether possible changes in GABA, benzodiazepine receptors and choline acetyltransferase (ChAT) activity are implicated in the pathophysiology of these animals. 2. No alteration in GABAA and GABAB binding could be detected in cerebellar membranes of epileptic mice as compared to normal mice. 3. Benzodiazepine receptor density and affinity showed no statistical difference in cerebellar membranes of epileptic and normal mice. 4. The activity of ChAT determined in the cortices of epileptic and normal mice did not differ significantly between the two groups.

Acetylcholine↗
PubMed1986

Neuronal sensitivity to GABA and glutamate in generalized epilepsy with spike and wave discharges.

In awake but painlessly immobilized cats the extracellular activity of the same cortical neurons was recorded before and for 2 to 5 h after the injection of penicillin G (350,000 IU/kg, i.m.) during the development of generalized epilepsy with bilaterally synchronous spike and wave discharges. Possible changes in their sensitivity to microiontophoretically applied glutamate and GABA during this period were searched for using computer-generated periejection histograms at intervals of about 30 min. In contrast to reported studies in other models of epilepsy, glutamate excited and GABA depressed virtually all neurons tested during fully developed spike and wave epilepsy. Spike height was not apparently affected either by the amino acids or by the development of epilepsy. Comparison of relative thresholds for the above effects on rhythmical neuronal activity associated with spike and wave discharge versus effects on random neuronal activity during the interburst periods, supported the idea that spikes and waves result from strong excitatory and inhibitory synaptic drives of the neurons. In all neurons until the appearance of spike and wave discharges, changes in the effect of amino acids, if observed, were small and statistically nonsignificant. This suggests that the hyperexcitability of cortical neurons which reportedly leads to the appearance of spike and wave discharges depends on mechanisms other than an increase in sensitivity to glutamate or a desensitization to GABA. Sometimes the sensitivity to GABA decreased later in this experimental model when the very frequent appearance of spike and wave discharges eventually led to EEG tonic-clonic seizures.

Animals↗
PubMed1985

Intracortical inhibitory mechanisms are preserved in feline generalized penicillin epilepsy.

Intracortical inhibition elicited by direct cortical stimulation or by stimulation of the cerebral peduncle, the latter inducing recurrent inhibition of cortical neurons, is not significantly affected by intramuscular injection of penicillin sufficient for inducing the syndrome of feline generalized penicillin epilepsy characterized by generalized spike and wave (SW) discharges in the EEG. This raises to four the number of paradigms of presumably postsynaptic inhibition resistant to penicillin concentrations sufficient to produce generalized SW discharges, a form of epileptic discharge which thus cannot be attributed to blockage of the forms of intracortical postsynaptic inhibition so far tested.

Animals↗
PubMed1984

Computer assisted analysis of relations between single-unit activity and spontaneous EEG.

Two mutually complementary computer methods are described which can be used for the study of unit-EEG relationships during spontaneous EEG waves. The first one consists of using the unit activity to trigger the averaging of sections of EEG preceding and following each unit; the same unit activity is used for building a histogram of unit firing from another cell. Sections of data subjected to this analysis need not be continuous; they may be chosen interactively on the computer terminal, thus allowing to analyze intermittent phenomena. The second method consists of using a particular point of an EEG wave to trigger EEG averages from other channels as well as unit histograms. Here again the waves are chosen interactively. The unit-triggered EEG averages are more objective and less time consuming. However, they do not describe accurately the characteristics of the individual wave to which a unit firing is associated and also they give no information about inhibitory phenomena. Both these drawbacks are corrected by the wave-triggered unit histograms where the experimenter interactively selects and stores for analysis EEG waves with the appropriate characteristics. Several examples are given from the utilization of these programs in neurophysiological and neuropharmacological experiments, with special emphasis on generalized epilepsy.

Animals↗