Feline generalized penicillin epilepsy represents an experimental model of generalized spike-and-wave discharges occurring during clinical absence attacks. Spike-and-wave discharges of feline generalized penicillin epilepsy also have a pharmacological profile that is similar to that encountered in human absence attacks. Studies on the respective roles played by the thalamus and cortex in the generation of spike-and-wave discharges indicate that both structures are important in the elaboration of such generalized activity. Moreover, GABAA-mediated, intracortical inhibitory mechanisms are preserved and eventually enhanced at a time when generalized spike-and-wave discharges of feline generalized penicillin epilepsy are recorded. A preservation of GABA-mediated mechanisms in pure absence epilepsy might explain the differences in prognostic outlook that characterizes this type of epilepsy from seizures in which GABAergic mechanisms break down (e.g., generalized convulsive and partial epileptic attacks).

Animals↗

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Failure of the antiepileptic drug valproic acid to modify synaptic and non-synaptic responses of CA1 hippocampal pyramidal cells maintained 'in vitro'.

The mechanisms of action of the antiepileptic drug valproic acid (VPA) were analyzed in 24 CA1 pyramidal neurons of the 'in vitro' hippocampal slice by using standard intracellular recording techniques. VPA (0.5-2 mM) failed to induce any significant change in the amplitude of the orthodromic EPSPs and the amplitude and duration of the IPSPs evoked by orthodromic or antidromic stimuli. The repetitive firing induced by depolarizing current pulses and the subsequent long lasting afterhyperpolarization were also not affected by VPA. We conclude that VPA, at doses within the therapeutic range, does not potentiate GABA-mediated inhibition in this preparation and probably acts on mechanisms which are not operating or fully expressed in normal (i.e., non-epileptic) situations.

Action Potentials↗

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Repetitive low-frequency stimulation reduces epileptiform synchronization in limbic neuronal networks.

Deep-brain electrical or transcranial magnetic stimulation may represent a therapeutic tool for controlling seizures in patients presenting with epileptic disorders resistant to antiepileptic drugs. In keeping with this clinical evidence, we have reported that repetitive electrical stimuli delivered at approximately 1 Hz in mouse hippocampus-entorhinal cortex (EC) slices depress the EC ability to generate ictal activity induced by the application of 4-aminopyridine (4AP) or Mg(2+)-free medium (Barbarosie, M., Avoli, M., 1997. CA3-driven hippocampal-entorhinal loop controls rather than sustains in vitro limbic seizures. J. Neurosci. 17, 9308-9314.). Here, we confirmed a similar control mechanism in rat brain slices analyzed with field potential recordings during 4AP (50 microM) treatment. In addition, we used intrinsic optical signal (IOS) recordings to quantify the intensity and spatial characteristics of this inhibitory influence. IOSs reflect the changes in light transmittance throughout the entire extent of the slice, and are thus reliable markers of limbic network epileptiform synchronization. First, we found that in the presence of 4AP, the IOS increases, induced by a train of electrical stimuli (10 Hz for 1 s) or by recurrent, single-shock stimulation delivered at 0.05 Hz in the deep EC layers, are reduced in intensity and area size by low-frequency (1 Hz), repetitive stimulation of the subiculum; these effects were observed in all limbic areas contained in the slice. Second, by testing the effects induced by repetitive subicular stimulation at 0.2-10 Hz, we identified maximal efficacy when repetitive stimuli are delivered at 1 Hz. Finally, we discovered that similar, but slightly less pronounced, inhibitory effects occur when repetitive stimuli at 1 Hz are delivered in the EC, suggesting that the reduction of IOSs seen during repetitive stimulation is pathway dependent as well as activity dependent. Thus, the activation of limbic networks at low frequency reduces the intensity and spatial extent of the IOS changes that accompany ictal synchronization in an in vitro slice preparation. This conclusion supports the view that repetitive stimulation may represent a potential therapeutic tool for controlling seizures in patients with pharmaco-resistant epileptic disorders.

Animals↗

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Cesium potentiates epileptiform activities induced by bicuculline methiodide in rat neocortex maintained in vitro.

We report that extracellular application of cesium (Cs+, 3 mM) potentiated the epileptiform discharge evoked by GABAA-receptor antagonist bicuculline methiodide (BMI 50 microM) in rat neocortical slices maintained in vitro. Cs+ changed BMI-induced epileptiform burst of a few hundred milliseconds evoked by extracellular focal stimuli into epileptiform discharge only a few seconds long (1.8-7 s). Moreover, Cs+ induced the appearance of spontaneously occurring epileptiform activities (0.038-0.15 Hz). Simultaneous intracellular/extracellular recordings indicated that each intracellular epileptiform burst was correlated with a field discharge. Variation of the membrane potential modified only the amplitude of the epileptiform burst and did not alter its frequency of occurrence, indicating that each discharge was a synchronous population event. The epileptiform discharges were not blocked by the N-methyl-D-aspartate (NMDA) receptor antagonist 3-((+-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP 5-10 microM). In contrast, the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX 0.5-5 microM) greatly reduced the duration of each epileptiform discharge by abolishing its afterdischarges in a concentration-dependent manner. This reduction in duration was accompanied by an increase in frequency of occurrence, however. After blockade of non-NMDA receptors with CNQX, a CPP-sensitive spontaneous discharge could be observed. These findings indicate that the inorganic cation Cs+ applied extracellularly can induce spontaneously occurring epileptiform activities in BMI-treated neocortical slices. In addition, receptors of excitatory amino acids play a major role in synchronizing this type of Cs+/BMI-induced spontaneous epileptiform activities.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMedDate not supplied

Induction of epileptiform activity by temperature elevation in hippocampal slices from young rats: an in vitro model for febrile seizures?

Extracellular field potential recordings were performed in the CA1 subfield of hippocampal slices obtained from Wistar rats aged 2-38 days. When the brain tissue was maintained at 35 degrees-36 degrees C (values obtained in the tissue chamber well), single-shock orthodromic stimuli elicited a response in the stratum pyramidale that consisted of a single population spike. In contrast, when the temperature in the well was increased to levels greater than 38.2 degrees C for periods of 5-15 min, the same type of stimuli elicited an epileptiform response characterized by a 250- to 600-ms-long, positive-going field potential with superimposed, multiple, negative-going population spikes. This potential resembled the epileptiform response recorded in the hippocampal slice in the presence of convulsants such as penicillin or bicuculline. Once the temperature was restored to control values (i.e., 35 degrees-36 degrees C) after induction of epileptiform activity, the abnormal response could be observed for less than or equal to 2 h. In some experiments (approximately one third of the successful trials), spontaneous epileptiform discharges appeared during and persisted after the increase in temperature. The ability of the hyperthermic period to induce epileptiform changes was age dependent: Epileptiform activity outlasting the period of temperature elevation was not observed in slices obtained from rats aged less than 4 days or greater than 28 days. Our data show that epileptiform activity can be induced by a transient increase in temperature and that the age of the animals from which slices are obtained plays an important role in the appearance of this phenomenon.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗