SUSCEPTIBILITY TO FOCAL AND GENERALIZED SEIZURES IN WISTAR RATS WITH GENETIC ABSENCE-LIKE EPILEPSY S. BRAILOWSKY,*² T. MONTIEL,* A. BOEHRER,‡ C. MARESCAUX‡ and M. VERGNES‡§ *Instituto de Fisiologı ´a Celular, Universidad Nacional Auto ´noma de Me ´xico, Me ´xico City, Me ´xico ‡INSERM U-398, Faculte ´ de Me ´decine, 11, rue Humann, Strasbourg 67000, France Abstract —The susceptibility to develop cortically induced focal and generalized seizures was examined in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), an inbred strain of Wistar rats with absence epilepsy. A GABA-withdrawal syndrome induced after suppression of a 2-h intracortical GABA infusion was used as a model of focal epileptogenesis: localized cortical discharges appear at the infusion site within 1 h. GAERS were more prone to develop a GABA-withdrawal syndrome than non- epileptic inbred controls and non-selected Wistar rats. After a transient suppression of absence seizures following GABA infusion in GAERS, generalized spike-and-wave discharges and focal spikes were recorded simultaneously in the cortex. GAERS also showed a higher incidence of systemic pentylenetetrazol-induced convulsions at the dose of 25 mg/kg. Higher doses had similar convulsant effects in all groups. In conclusion, the results confirm a genetic susceptibility in GAERS and/or resistance in inbred non-epileptic rats to focal and generalized seizures involving the cortex. Rats with absence epilepsy appear to be more prone to seizures elicited by cortical GABA deficiency.  1999 IBRO. Published by Elsevier Science Ltd. Key words: absence epilepsy, focal epileptogenesis, pentylenetetrazol, cerebral cortex, GABA-withdrawal syndrome. Absence epilepsy is a non-convulsive form of generalized epilepsy. Absence seizures are characterized by an abrupt loss of consciousness, of sudden onset and termination, and associated with a typical electroencephalogram (EEG) consisting of bursts of bilateral and synchronous spike-and- wave discharges (SWDs). 15 Absence seizures are a form of idiopathic generalized epilepsy and are defined as those in which there are no underlying causes other than a possible inherited predisposition. 11 Among the various genetic models of absence seizures available, the selected Wistar rats with spontaneous SWDs, named GAERS (Genetic Absence Epilepsy Rat from Stras- bourg) fulfill the criteria to be considered as a valid model of human absence epilepsy. 12 They show behavioral, electrophy- siological and pharmacological resemblances to human patients. The thalamus and cerebral cortex constitute the substrate of the EEG signature of this form of generalized, non-convulsive epilepsy: the hypersynchronous SWD. 7,15 GABAergic neurotransmission was shown to be critically involved in SWDs of genetic absence seizures (reviewed in Ref. 7). From the same Wistar strain, and using EEG criteria and inbreeding procedures, a non-epileptic control (NEC) strain was selected, hence becoming the control strain for the experimental study of GAERS. The basic mechanisms differentiating these strains are still unknown. Both strains are similar in appearance, behavior, baseline or interictal EEG and gross brain morphology. In 1987, working with a different animal model of genetic epilepsy, the photosensitive baboon, we discovered a para- doxical response to intracerebral microinjections of GABA, the predominant inhibitory neurotransmitter in the brain. Soon after cessation of GABA infusion, all animals showed high-amplitude paroxysmal discharges localized at the infu- sion site: this phenomenon was called the GABA-withdrawal syndrome (GWS) and has subsequently been confirmed in non-epileptic baboons, and in amygdala-kindled and normal rats. 1 The GWS is a GABA A receptor-dependent phenom- enon, as it can be induced with the GABA A agonist isoguva- cine, 3 but not with baclofen, a GABA B receptor agonist, 4 nor with taurine or glycine. Cortical hyperexcitability was suggested to account for spontaneous and experimentally induced absence seizures (for review see Ref. 7). We examined, in a genetic model of absence epilepsy, the possibility of enhanced cortical reactiv- ity to suppression of GABAergic inhibition, which would result in a facilitated generation of seizure activity. Therefore, we compared the responses of GAERS and NEC rats to intra- cortical microinfusion of GABA and its withdrawal, i.e. their susceptibility to develop a GWS. The induced changes in the spontaneous occurrence of SWDs were also noted. In another experiment, the convulsant potency of systemically adminis- tered pentylenetetrazol, a widely used convulsant agent 6,8 with antagonistic properties at GABA A receptors, was compared in GAERS and in two strains of non-epileptic rats: the inbred NEC and a Wistar strain of non-selected animals, originating from commercially purchased rats and bred locally at the University of Mexico (UNAM). EXPERIMENTAL PROCEDURES All animals were male Wistar rats, four to seven months of age, reared in the animal facility of the IFC-UNAM, under standard condi- tions of light (12-h/12-h light–dark cycle, light on at 7.00 a.m.), with food and water freely available. GAERS and NEC rats were derived GABA withdrawal, pentylenetetrazol and absence epilepsy 1173 1173 Neuroscience Vol. 93, No. 3, pp. 1173–1177, 1999 Copyright  1999 IBRO. Published by Elsevier Science Ltd Printed in Great Britain. All rights reserved 0306-4522/99 $20.00+0.00 PII: S0306-4522(99)00227-4 Pergamon ²We regret the unexpected death of our dear colleague Simon Brailowsky after submission of this manuscript. §To whom correspondence should be addressed. Tel.: +33-03-88-24-33- 63; fax: +33-03-88-24-33-60. E-mail address: Vergnes@neurochem.u-strasbg.fr (M. Vergnes) Abbreviations: EEG, electroencephalogram; GAERS, Genetic Absence Epilepsy Rat from Strasbourg; GWS, GABA-withdrawal syndrome; NEC, non-epileptic control; SWD, spike-and-wave discharge; UNAM, Universidad Nacional Auto ´noma de Me ´xico.