The GABA-Withdrawal Syndrome: A Model of Local Status Epilepticus

Neural Plasticity, Jul 2018

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 neocorticai 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 receptormediated 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.

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The GABA-Withdrawal Syndrome: A Model of Local Status Epilepticus

International Journal of The GABA-Withdrawal Syndrome: A Model of Local Status Epilepticus Carmen Silva-Barrat Jean Champagnat Christian Menini SUMMARY - For several years, our group in Gif-sur-Yvette (France) worked on a model of reflex epilepsy, the photosensitive epilepsy of Papio papio baboons (Killam et al. 1967) . When these predisposed baboons are submitted to intermittent light stimulation, generalized paroxysmal manifestations appear in the frontal motor cortex (Morrell et al., 1969) . We had clearly demonstrated that generalized paroxysmal manifestations originate in the motor cortex (Silva-Barrat et al. 1988) , when Simon Brailowsky came to our laboratory. Simon proposed to block the epileptic manifestations of baboons by means of a chronic infusion of ],-aminobutyric acid (GABA) into the motor cortex of these animals. We performed 4- to 7-day infusions by means of osmotic minipumps and observed the disappearance of epileptic manifestations. After cessation of the GABA infusion, however, a rebound of brain excitability was observed, as evidenced by the presence of epileptogenic discharges localized in the infused area (Bmilowsky et al., 1987; 1989). The phenomenon appearing after the interruption of the chronic GABA infusion was named the "GABAwithdrawal syndrome" (GWS). Initially, we demonstrated that GWS is not the consequence of the genetic epileptic predispositon of baboons, and we tested the effects of chronic intracortical GABA infusions in non-photosensitive animals. Indeed, we reproduced GWS not only in nonepileptic baboons but also in normal rats. After returning to Mexico, Simon and his group reproduced GWS in hippocampal slices of rats (Garciaugalde et al., 1992). Finally, this phenomenon could be considered a new model of focal epilepsy (Brailowsky et al., 1988) . Thanks to this discovery, a new series of epileptic studies has been initiated that we want to present briefly as our tribute to Simon. GWS AS A MODEL OF LOCAL STATUS EPILEPTICUS IN THE RAT: IN VIVO AND IN VITRO STUDIES. Both EEG and clinical studies (Brailowsky et al., 1988) have established that GWS is a status epilepticus resembling the epilepsia partialis continua, a partial status epilepticus that was described in human patients by Kojewnikow (1895). GABA is infused into the motor cortex of rats for 5 days. Upon cessation of the infusion, an epileptogenic focus appears, characterized by continuous EEG discharges at high frequency, localized in the infused area and associated with myoclonic twitches ofthe contralateral corresponding body territory. The epileptic manifestations appear 20 min after the infusion interruption, persist for 48 h on average, and never generalize into tonicclonic seizures. GWS is an interesting model resulting from a local manipulation that is associated with a focal epilepsy. GWS is different from other epilepsy models that are provoked by topical application of toxic or irritant drugs or even convulsant drugs (such as penicillin, kainate or pilocarpine) provoking diffuse abnormalities. Using conventional intracellular recording and stimulation techniques, we studied neuronal activity in the epileptogenic focus in neocortical slices obtained from rats presenting GWS (SilvaBarrat et al., 1989). The presence of a great number of burst-generating neurons in an area close to the GABA-infused site has enabled the analysis of epileptic-like pattern generation by comparing bursting and nonbursting cells. Bursting neurons present paroxysmal depolarizing shifts (PDSs) and bursts of action potentials (APs) after synaptic activation by white matter stimulation (WM) and/or intrinsic bursts of APs after intracellular injection with a depolarizing current. Nonbursting neurons present neither synaptic nor intrinsic bursting properties. In this paper, we will first describe the cellular types recorded in the GWS epileptic focus, and we will show that the bursting cells are desensitized to GABA. We will also present some ionic mechanisms that are involved in the genesis of the epileptic activity, and finally discuss some neuromodulatory mechanisms involved in this activity. PHYSIOLOGICAL AND MORPHOLOGICAL IDENTIFICATION OF NEURONS SHOWING BURSTING ACTIVITY Histological observation of slices showed that the recorded cells are impaled at the periphery of the necrotic zone (0.7 to 1.2 mm) because of cannula penetration and GABA infusion. The soma of biocytine-labeled neurons are localized in layer V (Fig. 1A). Cells presenting synaptic and/or intrinsic bursts have a pyramidal-shaped soma with a basal dendritic arborization, an apical dendrite, and an axon from the basal region of the soma (Fig. 1B) (Silva-Barrat et al., 1994) . Synaptic bursts are evoked by suprathreshold white matter stimulation. The bursts consist of 38 APs riding on the large depolarizing wave or PDS, EPSPs are obtained by decreasing the stimulus intensity to values subthreshold for AP elicitation (Fig. 1C). Intrinsic bur (...truncated)


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Carmen Silva-Barrat, Jean Champagnat, Christian Menini. The GABA-Withdrawal Syndrome: A Model of Local Status Epilepticus, Neural Plasticity, 7, DOI: 10.1155/NP.2000.9