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G Kostopoulos

Publications and source records attributed to G Kostopoulos.

At least 37 records · Page 2Linked to original sources

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↗

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↗

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↗

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↗

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↗

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↗

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↗

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↗

The mechanisms underlying potentiation of recruiting responses may include GABA-disinhibition.

Potentiation of recruiting responses has been demonstrated to occur in the course of development of generalized epilepsy in the cat (Kostopoulos and Avoli 1983). A similar potentiation of RR of cortical neurons was demonstrated here after microiontophoretic application of bicuculline. The release of cortical neurons from a GABA-mediated inhibition or another mechanism more sensitive to bicuculline may underly both these phenomena.

Animals↗

Enhanced response of cortical neurons to thalamic stimuli precedes the appearance of spike and wave discharges in feline generalized penicillin epilepsy.

Peristimulus time histograms of extracellularly recorded action potential discharges of cortical neurons in response to single shock and/or repetitive stimulation of 'specific' and 'non-specific' nuclei of the thalamus were studied after i.m. penicillin injection during a period corresponding to that of the development of spike and wave (SW) discharges of feline generalized penicillin epilepsy (FGPE). After i.m. penicillin cortical neurons displayed an enhancement of both the excitatory and 'inhibitory' phases of their responses to single shock stimulation of n. centralis medialis (NCM). This increase was even more pronounced for responses induced by repetitive stimulation of NCM at the frequencies inducing typical recruiting responses. These changes always preceded the appearance of SW discharges. Changes of the responses of cortical neurons to single shock and repetitive stimulation of 'specific' thalamic nuclei after penicillin were weak and inconsistent, although when observed were characterized by an enhancement of both excitatory and 'inhibitory' phases. The latter appeared not to decrease after i.m. penicillin. These data suggest that the appearance of SW discharges of FGPE is closely related to an increased responsiveness of cortical neurons to thalamocortical volleys arising from the so-called 'non-specific' nuclei. This facilitation of the recruiting process is accompanied by an increase of both excitatory and 'inhibitory' phases of the cortical neuronal responses induced by the volleys.

Animals↗

Participation of cortical recurrent inhibition in the genesis of spike and wave discharges in feline generalized penicillin epilepsy.

Cortical recurrent inhibition (RI) evoked in pericruciate cortex by antidromic stimulation of the cerebral peduncle (CP) was studied in normal cats and in cats exhibiting the signs of feline generalized penicillin epilepsy (FGPE) following the i.m. injection of penicillin. Two measures of RI evoked by antidromic CP stimulation were used: (i) the averaged focal potential in the pericruciate gyrus; and (ii) the duration of the suppression or diminution of extracellularly recorded action potential (ap) discharge of antidromically activated pericruciate neurons measured in peristimulus time histograms (PSTHs). After i.m. injection of 350,000 IU/kg of penicillin RI remained preserved as long as only generalized spike and wave (SW) discharges appeared in the EEG, although in 5/17 neurons a modest to moderate reduction in the duration of RI occurred once SW discharges had appeared in the EEG. This inconstant reduction was probably not caused by a direct anti-inhibitory action of penicillin, but is a consequence of the increased number of ap discharges curtailing RI. At the small concentrations of penicillin existing in brain in FGPE its anti-inhibitory action evident with larger concentrations cannot be demonstrated. When focal or generalized tonic-clonic (T-C) seizures occurred, RI was reduced in slightly more than half of the instances for a few minutes before the onset of these seizures. This suggests that the transition from SW discharge to T-C seizure may be caused by a breakdown of RI.

Animals↗

An analysis of penicillin-induced generalized spike and wave discharges using simultaneous recordings of cortical and thalamic single neurons.

To study the relationship between cortical and thalamic single-neuron activity during spike and wave (SW) discharge of feline generalized penicillin epilepsy (FGPE), extracellular single-unit and local electroencephalogram (EEG) activity were recorded simultaneously from pairs of neurons, one located in the cortex of the middle suprasylvian gyrus (MSS), the other in the dorsal thalamic nuclei (n. lateralis posterior or pulvinar). These two areas are anatomically and functionally closely interrelated. Computer-generated EEG averages and histograms of single-unit activity triggered by either peaks of cortical or thalamic EEG transients or by cortical or thalamic action potentials (aps) showed that cortical neurons in the MSS fired at the time of the spike of the SW complex, while at the time of the wave they became silent. Two populations of thalamic neurons also fired maximally during the spike of SW discharge, but they differed in the precise timing of their firing in relation to that of the simultaneously recorded cortical neuron. The first group of thalamic neurons tended to fire 5-45 ms before the cortical neuron. Of these 28 neurons, 9 were antidromically and 2 orthodromically activated by cortical stimulation. The neurons of the second group tended to fire 0-45 ms after the cortical neuron. Cortical stimulation activated 15 of these 19 neurons orthodromically and 2 antidromically. A third and smaller population of thalamic neurons (n = 8) increased its firing probability during the wave of the SW complex and decreased it during the spike. In 74% of the pairs of neurons the cyclic alternation of excitation and "inhibition" associated with SW activity appeared in the cortex by 1-3 cycles earlier than in the thalamus. This was most common when the thalamic neuron of the pair reached its peak firing probability before the simultaneously recorded cortical neuron. In 11 pairs of neurons the same rhythmic alternation of excitation and "inhibition" of neuronal firing was seen in both the cortex and thalamus during SW discharges evoked by single-shock stimulation of nucleus centralis medialis. These data demonstrate that both cortical and thalamic neurons participate in the SW firing pattern of FGPE by undergoing periods of mutually phase-locked cyclic alternations of excitation and "inhibition" at the frequency of the EEG SW rhythm. Although the initial steps leading to generalized SW discharge in FGPE take place in the cortex, the thalamus soon becomes entrained in the SW rhythm.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

Participation of corticothalamic cells in penicillin-induced generalized spike and wave discharges.

Single unit extracellular recordings were performed in the cortex of awake painlessly immobilized unanesthetized cats during generalized spike and wave discharges (SW) induced by i.m. penicillin. Corticothalamic cells were identified in cortical areas 3a and 4 gamma by stimulating n. ventralis lateralis (VL) and in cortical areas 5 and 7 by stimulating n. lateralis posterior (LP). Twelve of 24 neurons antidromically invaded from VL were also pyramidal tract cells. Two of 11 neurons antidromically invaded from LP also displayed orthodromic responses. Corticothalamic cells fired bursts of action potentials in association with the 'spike' whereas a period of inhibition was associated with the 'wave' of the SW complex. The data suggest that in this experimental model the appearance of SW in the thalamus is due to secondary activation of thalamic neurons by volleys arising from the cortex and mediated through corticothalamic connections.

Animals↗

Potentiation and modification of recruiting responses precedes the appearance of spike and wave discharges in feline generalized penicillin epilepsy.

Recruiting responses (RR) were evoked by stimulation of nucleus centralis medialis in awake and painlessly immobilized cats. Following the administration of sodium penicillin G (350,000 IU/kg i.m.) and at a time preceding the development of generalized spike-and-wave discharge we observed a strong potentiation of RR in 10 out of 15 experiments (50-200% increase in amplitude). The major feature of wave form modification consisted mainly of a development or increase of positive phases of individual recruiting waves. In between such large amplitude negative-positive recruiting waves a slow negative wave developed. One of every two recruiting waves was often diminished when the preceding recruiting wave had reached considerable amplitude. The changes in the RR were antagonized by barbiturates and by caffeine. In conjunction with previous evidence these results support the hypothesis that spikes of spike-and-wave discharges in FGPE are generated by similar thalamocortical volleys as those creating RR and spindles. They further suggest that the crucial neuronal mechanism underlying this effect of penicillin is a shift in the emphasis from distal apical dendritic thalamocortical synapses on cortical pyramidal neurons to more proximal ones.

Action Potentials↗

Laminar analysis of spindles and of spikes of the spike and wave discharge of feline generalized penicillin epilepsy.

Intracortical laminar profiles of spindles and spikes of spike and wave complexes in feline generalized penicillin epilepsy were studied using two methods: (i) sequential microelectrode recordings at various cortical depths, and simultaneous recordings at multiple cortical depths using a fine multi-contact electrode. Raw EEG data and EEG epochs averaged with respect to peaks of surface EEG waves were analyzed. Spindles and the spikes of the spike and wave complexes showed similar laminar profiles. This supports the hypothesis that the two are basically the same cortical electrophysiological phenomenon, the spike being a spindle wave enhanced and slightly altered because of the penicillin-induced increased cortical excitability. The latter causes the weight of the thalamic input to shift from superficial to more deep lying synapses. Both surface negative and surface positive phases of spindles and of spikes of spike and wave complexes show similar laminar profiles, those of the former suggesting activation of excitatory synapses in the superficial cortical layers, those of the latter suggesting activation of more deeply located excitatory synapses. The profiles generally conform to the dipole hypothesis of cortical electrogenesis and suggest that spindles and spikes of spike and wave complexes are generated by the same pyramidal neurons, probably through activation of the same sets of synapses. Some inconstant and relatively minor deviations of the laminar profiles from the pattern predicted by the dipole theory of cortical electrogenesis were encountered and are tentatively explained in the light of some of the complexities of the microanatomical organization of mammalian neocortex.

Action Potentials↗

Effects of post-ictal depression on experimental spike and wave discharges.

The effects of post-ictal depression on spike and wave (SW) discharges of feline generalized penicillin epilepsy (FGPE) were studied. After tonic-clonic seizures which are not uncommon in FGPE spindle bursts appeared during the post-ictal period. Upon recovery spontaneous and thalamically evoked SW discharges reappeared. Spindles before penicillin and during post-ictal depression showed a similar intraburst frequency (twice that of SW discharges) in the same animal. These findings add further evidence to the notion that any depression of cortical excitability in FGPE leads to replacement of SW by spindles and thus supports the hypothesis that SW discharges occur in hyperexcitable cortex in response to normally spindle-inducing thalamocortical volleys.

Animals↗