Mechanisms of generalized epilepsy with spike and wave discharge

S16 tissue hyperexcitability. Mechanisms of abnormal cell discharge, particularly during interictal-like events, have been examined with extra- and intracellular techniques in acute and chronic preparations, in vivo and in vitro. It is clear that subtle alterations in intrinsic and synaptic properties, and in extracellular milieu, can lead to epileptiform discharge. The basic mechanisms of neuronal hyperexcitability may be encompassed within two major categories: 1) loss of normal inhibitory efficacy and 2) changes in the balance between inward currents (sodium and calcium) and outward currents (usually potassium). Both types of processes can lead to abnormal repetitive discharge in cortical and hippocampal neurones. Mechanisms accounting for increased neuronal synchrony during epileptiform activities are not so well understood. Increased efficacy of excitatory or inhibitory interneuronal circuits, or exaggerated effects of direct interconnections among pyramidal cells seems likely in primary foci (i.e., where projected activity cannot account for the synchrony). Developing ephaptic effects may also contribute to synchronization of neuronal populations. Recent studies have suggested that positive feedback, via long loop circuits, can be critical for the development of focal epileptiform activity, as well as for its generalization. Our studies of models of focal epileptiform activities have yielded a large number of possible mechanisms of epileptogenesis. Validation of these models, and assessment of potential underlying pathophysiological processes, must now be carried out using clinically-relevant material.

S 9.02 M E C H A N I S M S OF GENERALIZED EPILEPSY WITH SPIKE A N D WAVE DISCHARGE. M. Avoh

passive follower of the cortex in SW activity since thalamocortical inputs remain necessary to maintain it. Data gathered with this model suggest that the substrate of generalized SW discharge is the oscillatory activity within a closed thalamocorticothalamic loop made more effective by systemic penicillin.

S 9.03 N E U R O T R A N S M I T T E R A M I N O ACIDS IN EPILEPSY. B. M e l d r u m

(London, UK) Inhibitory and excitatory amino acid neurotransmitters are involved in the initiation, spread and termination of seizure activity. The role played by GABA, glycine and taurine or by glutamate, aspartate, cysteine sulphinate and quinolinate in the pathogenesis of different forms of epilepsy is still uncertain. Experimentally, seizures may be induced by blockade of GABAergic inhibition, or by activation of excitatory amino acid receptors. Seizures may be prevented or diminished by pharmacological treatments that enhance GABAergic transmission e.g.GABA agonists and prodrugs, GABA uptake inhibitors, G A B A transaminase inhibitors, allosteric enhancement of the inhibitory action of G A B A by benzodiazepines or anticonvulsant b-carbolines, direct actions on the chloride ionophore by barbiturates, etc. Seizures may also be prevented by drugs that impair excitatory transmission. In particular, antagonists that block excitation at the N-methyl-D-aspartate preferring receptor, such as 2-amino-7-phosphonoheptanoic acid, are anticonvulsant in many animal test systems. Selective blockade of excitatory transmission provides a novel approach to anticonvulsant drug therapy.

(Montreal, Canada) Generalized epilepsy induced in cats by the intramuscular injection of penicillin represents an experimental model suitable for studying the electrophysiological mechanisms underlying generalized spike and wave (SW) discharges. These are the EEG concomitant of the absence attack of primary generalized epilepsy in humans. Different types of experiments to be reviewed in this presentation suggest that penicillin-induced SW discharges depend upon both cortical and thalamic mechanisms. Cortical neurones, under the influence of systemic penicillin become more excitable and respond more vigorously to thalamocortical volleys normally inducing spindles. This increased neocortical response activates repolarizing currents, including phasic inhibitory ones, which are in fact preserved at this low concentration of penicillin in the brain. An oscillation between periods of increased and decreased neuronal firing probability ensues which underlies the EEG SW discharge. The cortex imposes this oscillatory pattern of neuronal discharge upon the thalamus, which by itself is incapable of responding in this way to systemic penicillin. Nevertheless the thalamus is not a mere

S 9.04 A N T I C O N V U L S A N T D R U G M E C H A N I S M S OF ACTION. R.L. Macdonald and M.J. McLean

(Ann Arbor, MI, USA) Anticonvulsant drugs are classified by their efficacy against specific clinical seizure types. Carbamazepine and phenytoin are effective against generalized tonic/clonic seizures and some forms of partial seizures but have no activity against generalized absence seizures. In contrast, ethosuximide is highly selective for generalized absence seizures. This selectivity of clinical actions suggests that clinically used anticonvulsant drugs also have specific mechanisms of action. We have used mouse neurons in cell culture to study the actions of anticonvulsant drugs on synaptic transmission and membrane excitability. We have proposed that at least two mechanisms may be responsible for their anticonvulsant efficacy: limitation of sustained high-frequency repetitive firing of action potentials and en-