Muscarinic depression of synaptic transmission in the epileptogenic GABA withdrawal syndrome focus.

The GABA withdrawal syndrome (GWS) is a model of local status epilepticus consecutive to the interruption of a prolonged GABA infusion into the rat somatomotor cortex. Bursting patterns in slices from GWS rats include intrinsic bursts of action potentials (APs) induced by intracellular depolarizing current injection and/or paroxysmal depolarization shifts (PDSs) induced by white matter stimulation. Possible changes in the effects of cholinergic drugs after in vivo induction of GWS were investigated on bursting cells (n = 30) intracellularly recorded in neocortical slices. In GWS slices, acetylcholine (Ach, 200-1000 microM) or carbachol (Cch, 50 microM) applications increased the number of bursts induced by depolarizing current injection while synaptically induced PDSs were significantly diminished (by 50-60%) or even blocked independently of the cholinergic-induced depolarization. The intrinsic burst facilitation and PDS depression provoked by Ach or Cch were mimicked by methyl-acetylcholine (mAch, 100-400 microM, n = 11), were reversed by atropine application (1-50 microM, n = 3), and were not mimicked by nicotine (50-100 microM, n = 4), indicating the involvement of muscarinic receptors. In contrast, in nonbursting cells from the same epileptic area (n = 42) or from equivalent area in control rats (n = 24), a nonsignificant muscarinic depression of EPSPs was induced by Cch and Ach. The mAch depression of excitatory postsynaptic potential (EPSPs) was significantly lower than that seen for PDSs in GWS rats. None of the cholinergic agonists caused bursting appearance in these cells. Therefore the present study demonstrates a unique implication of muscarinic receptors in exerting opposite effects on intrinsic membrane properties and on synaptic transmission in epileptiform GWS. Muscarinic receptor mechanisms may therefore have a protective role against the development and spread of epileptiform activity from the otherwise-activated epileptic focus.

The GABA-withdrawal syndrome: a model of local status epilepticus.

The GABA-withdrawal syndrome (GWS) is a model of local status epilepticus following the interruption of a chronic GABA infusion into the rat somatomotor cortex. GWS is characterized by focal epileptic electroencephalographic discharges and associated contralateral myoclonus. In neocortical slices obtained from GWS rats, most neurons recorded in the GABA-infused area are pyramidal neurons presenting bursting properties. The bursts are induced by white-matter stimulation and/or intracellular depolarizing current injection and correlate with a decrease of cellular sensitivity to GABA, caused by its prolonged infusion. This effect is related to a calcium influx that may reduce the GABAA receptor-mediated inward current and is responsible for the bursting properties. Here we present evidence for the involvement of calcium- and NMDA-induced currents in burst genesis. We also report modulatory effects of noradrenaline appearing as changes on firing patterns of bursting and nonbursting cells. Complementary histochemical data reveal the existence of a local noradrenergic hyperinnervation and an ectopic expression of tyrosine hydroxylase mRNAs in the epileptic zone.

Low platelet glutathione peroxidase activity and serum selenium concentration in patients with chronic renal failure: relations to dialysis treatments, diet and cardiovascular complications.

1. Selenium status was investigated in patients with chronic renal failure, with special regard to its relations to the dialysis treatments, dietary habits and clinical signs of atherosclerosis. 2. Serum selenium concentration and platelet glutathione peroxidase activity were measured in 45 patients with chronic renal failure subdivided into three groups according to the type of treatment: 15 non-dialysed, 15 on haemodialysis, 15 on continuous ambulatory peritoneal dialysis. A 7-day diet history was carried out in all patients. Seventeen of the patients with chronic renal failure had clinically overt cardiovascular disease. Forty-five age-matched healthy subjects were considered as controls. 3. Both serum selenium concentration and platelet glutathione peroxidase were significantly reduced in all patients with chronic renal failure compared with control subjects; a direct and significant correlation was found between the two parameters. No differences in selenium status were observed among the non-dialysed, haemodialysis and continuous ambulatory peritoneal dialysis groups. No correlation between total calorie or protein intakes and selenium indices were observed. The chronic renal failure patients with cardiovascular complications showed a further significant reduction in both serum selenium concentration and platelet glutathione peroxidase activity as compared with the patients without cardiovascular complications; these two groups were similar with respect to the other well-known cardiovascular risk factors (age, smoking, plasma lipids, hypertension, body mass index). 4. It is concluded that a low selenium concentration is present in chronic renal failure, which is independent of dialysis and is accompanied by biological repercussion in terms of reduced platelet glutathione peroxidase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of localized, chronic GABA infusions into different cortical areas of the photosensitive baboon, Papio papio.

The effects of chronic (7 days) intracortical GABA infusions were investigated in both naturally photosensitive and non-photosensitive baboons. Bilateral and unilateral infusions into motor and occipital regions blocked photosensitivity, while premotor and prefrontal cortex infusions had no effect on the electro-clinical manifestations of this type of reflex epilepsy; the monkeys with prefrontal GABA infusions, however, showed selective attention deficits, detected with the delayed response test. In all cases a GABA withdrawal syndrome, appearing as epileptogenic spontaneous activity localized to the infused sites, was found at the cessation of GABA application. We conclude that GABAergic systems localized at discrete cortical areas play an important role in photosensitivity and in the modulation of cognitive processes in the monkey.

Anticonvulsant effects of localized chronic infusions of GABA in cortical and reticular structures of baboons.

We studied the effects of chronic (7 day) infusions of GABA (100 and 20 micrograms/microliter, 10 microliter/h) applied in different cerebral structures of baboons made photosensitive by a subconvulsant dose of allylglycine. The GABA infusion has partial anticonvulsant effects when applied to the motor cortex, reticular magnocellular nucleus (RMC), or substantia nigra (SN), but when directed to the prefrontal cortex (area 8) it has no effect. These anticonvulsant effects of GABA infusion are more important when GABA is infused into the motor cortex, where paroxysmal discharges (PDs) originate, than when it is infused into the RMC. In contrast, the anticonvulsant effects on light-induced generalized seizures are more pronounced when GABA is infused into the RMC than when it is infused into the motor cortex. GABA infusion into the SN has no effect on PDs and myoclonia and blocks seizures less effectively than the RMC infusion. These results are in accordance with the role of the motor cortex as a generator of PDs and of RMC in the generalization of seizures. Focal paroxysmal EEG and clinical activities, previously reported to appear at the end of the motor cortex GABA infusion, were not observed after RMC or SN infusions. However, behavioral hyperactivity occurring at the end of subcortical GABA infusions was observed. These behavioral signs could correspond to the clinical expression of a GABA withdrawal syndrome.

Epileptogenic gamma-aminobutyric acid-withdrawal syndrome after chronic, intracortical infusion in baboons.

We studied the effects of chronic (7 days) infusion of GABA (100 micrograms/microliter) applied intracortically into the fronto-rolandic (FR) area of baboons, via osmotic minipumps. In photosensitive animals, bilateral GABA application produced a complete blockade of the paroxysmal discharges and associated clinical signs induced by intermittent light stimulation. Unilateral administration had similar effects, although these developed more gradually. At the end of the infusion period, both photosensitive and non-photosensitive animals showed a transitory state (3-4 days) of cortical hyperexcitability (spontaneous epileptogenic activity) localized to the infused area. The data indicate a role of GABA both in the natural photosensitivity of the epileptic baboon and in the withdrawal syndrome consecutive to the sudden interruption of chronically enhanced GABA levels in the FR territories of this monkey.

Multiunitary activity analysis of cortical and subcortical structures in paroxysmal discharges and grand mal seizures in photosensitive baboons.

Cortical and subcortical multiunitary activities (MUA) and EEG were simultaneously recorded in baboons made photosensitive by a subconvulsant dose of DL-allylglycine. Intermittent light stimulation (ILS) trains induced in these animals fronto-rolandic (FR) paroxysmal discharges (PDs, constituted as spikes and waves) and grand mal seizures. During the induction of FR PDs by ILS trains, the visual structures (occipital cortex, colliculi superioris, pulvinar) showed a significant MUA increase which was not related to the PD spike or wave but correlated with the flashes. The first structure showing bursts of MUA that frequently preceded the PD appearance was the FR cortex. When PDs appeared, the bursts were related to the spikes of PDs and were followed by an inhibition during the slow wave. The pontine and mesencephalic reticular formations and the facial nuclei were activated in bursts after the FR PDs had reached a certain amplitude. The thalamic nuclei ventralis lateralis, centrum medianum and lateralis posterior were activated only later, when the FR PDs had reached an even greater amplitude. It is suggested that the activation of visual structures is necessary for FR PD appearance. The secondary pontine and mesencephalic activation could reinforce that of the FR cortex and then the thalamus, and could determine the myoclonus observed in unparalysed animals. When the ILS is continued, grand mal seizures appear. The onset of the seizures could be linked to the loss of FR cortical control of the subcortical structures. The resulting reticular activation would be responsible for the vasomotor modifications which constitute the first clinical signs of a seizure.

[Role of the thalamus in the physiopathology of epilepsy]. / Role du thalamus dans la physiopathologie des épilepsies.

Early hypotheses on the origin of primary generalized epilepsy suggested a determinant role for the "centrencephalon" in the triggering of discharges of generalized spike-waves (GSW) and tonic-clonic crises (TCC). It was demonstrated in this respect that bilateral cortical spike-wave discharges at 3 c/sec were obtained by electrical stimulation of intralaminar nuclei in the rat. The role of the thalamus in the genesis of GSW and TCC was subsequently demonstrated in several experimental models. However, the thalamus is apparently not involved in the genesis of EEG manifestations of generalized epilepsy and most authors agree that the latter are of cortical origin since a) with or without cardiazol, generalized seizures may occur after ablation of cat thalamus; b) in the cat diffuse cortical application of dilute penicillin can reproduce signs of generalized epilepsy observed after systemic injection of penicillin to this animal; c) finally paroxysmal discharges which appear in subcortical structures in the photosensitive baboon are always preceded by frontal cortical spike-waves; similarly intermittent light stimulation-provoked TCC always arise from the frontal cortex and furthermore hemispheric synchronization of attacks disappears after callosotomy. These findings indicate that the origin of GSW and TCC, is not in the thalamus but that the latter nevertheless plays a role in their elaboration.

Characteristics and origin of frontal paroxysmal responses induced by light stimulation in the Papio papio under allylglycine.

In the Papio papio, curarized and rendered photosensitive by injection of a subconvulsant dose of DL-allylglycine, single flashes induce frontal paroxysmal evoked responses on condition that they be preceded by trains of intermittent light stimulation (ILS). The characteristics of these responses have been compared to those of non-paroxysmal responses induced in the same cortical area by isolated flashes (not preceded by trains of ILS). The paroxysmal responses resemble spikes and waves and consist of one or two positive spikes followed by a slow negative wave. The intracortical distribution of these responses has been studied in the motor cortex. The non-paroxysmal responses are probably not generated at this level. On the other hand, observations made during paroxysmal responses show the existence of two cortical responses; this demonstration follows from the existence of an inversion in some response components, linked to a negativity and a local cellular activation. A generator, situated in the pyramidal cell layer, is active during the positive surface spikes; the other generator, situated in the more superficial cortical layers, is active at the beginning of the slow negative surface wave. The cortical and subcortical afferents likely to bring these generators into play are discussed.

Absence of seizure activity following focal cerebral injection of enkephalins in a primate.

Baboons (Papio papio) with photosensitive have been chronically prepared with guide cannulae and deep electrodes to study the effects of focal injections of opioids. In the hippocampus, amygdala and thalamus (centre median) 50--100 micrograms morphine, 20--100 micrograms Met-enkephalin or 2--10 micrograms FK 33,824 do not induce local or general electrographic or motor signs of epilepsy. The acute epileptogenic effect of morphine and enkephalins observed in rats is not a general phenomenon whereas the anticonvulsant action of opioids acting on mu-receptors is seen in rodents and primates.

Neurophysiology of photically induced epilepsy in Papio papio.

This chapter critically reviews arguments supporting the role of the frontal cortex in light-sensitive epilepsy of the baboon Papio papio in the light of the most recent neurophysiological research. In particular, it is known that spontaneous or ILS-induced paroxysmal discharges, as well as generalized seizures, originate in the frontorolandic cortical region. In this region during ILS, neurons behave in the same manner as hyperexcitable neurons in focal epileptogenic lesions of animals and man. Aso, section of the corpus callosum causes deterioration or even destruction of the synchronization that exists naturally between the two frontorolandic areas. Lastly experimental focal irritative lesions enhance light sensitivity if they are located in the frontorolandic region and inhibit it if they are located in the occipital cortex. Opposing these arguments are those that support the important role the occipital cortex plays, since its ablation makes excessive light sensitivity in the baboon disappear. Studies of the primary and nonprimary visual messages and pathways have also contributed evidence. In particular, demonstration of the existence of large numbers of direct occipitofrontal connections may help reconcile the two opposing arguments. Other evidence favoring the role of the frontal cortex is furnished by the still fragmentary studies on activation of the motor pathways and by studies in neuropharmacology. The significance and value of this type of epilepsy as an animal model of the generalized reflex epilepsies of man are discussed.