Ictogenesis

*Michel Le Van Quyen, †Pascale Quilichini, †Yehezkel Ben‐Ari, †Christophe Bernard, and †Henri Gozlan ( *Neurodynamics Group, LENA‐CNRS UPR640, Hôpital de la Salpêtrière, Paris , and †INMED‐INSERM U 29 Marseille, France ). Network oscillations in the gamma‐frequency band (40–100 Hz) have a central role in the transition to seizure. Here we analyzed spontaneous ictal‐like events (ILE) at distinct postnatal periods P1–P8 in intact rat corticohippocampal formations (CHF) exposed to low Mg2+ artificial cerebrospinal fluid (Quilichini et al., 2002). Quantitative time‐frequency analyses of field recordings showed that gamma oscillations can be observed very early at postnatal day (P) 3. Between P3–P5, spontaneous gamma oscillations were seen as brief bursts (<200 ms) at 30–60 Hz frequencies, superposed on slow epileptiform activities at the beginning of the ILE. After P6, the oscillations gained amplitude and extended also to higher frequencies (>100 Hz). The study of simultaneous recordings of various regions (CA1, CA3, dentate gyrus, neocortex, two interconnected CHF) showed that gamma oscillations primarily emerge in the hippocampal circuitries, but propagate to all other brain structures. Gamma oscillations persist after blockade of GABAA receptors by bicuculline or after blockade of glutamate receptors by CNQX. Furthermore, gamma oscillations are not sensitive to the gap junction blocker, carbonexolone. This suggests that an interactive network of interneurons may play a pivotal role in the gamma oscillations of early life seizures. Surprisingly, their generation seems not to be exclusively associated with GABAergic synaptic interactions or with electrotonic coupling. We conclude that intact and immature brain structures provide a unique opportunity to study in vitro the implication of gamma oscillations in ictogenesis, as well as their involvement in the production of chronic epileptic conditions. *James W.Y. Chen and *Arthur W. Toga ( *Department of Neurology, The David Geffen School of Medicine at UCLA, Los Angeles, CA, U.S.A. ). Purpose: It was noted in our study that optical intrinsic signal (OIS) imaging represents seizure activity with a high degree of correlation (Neurology 2000;55:312–5). Our group also reported triphasic OIS changes during cortical spreading depression (CSD) (NeuroReport 2000;11:2121–5). Our recent findings in OIS imaging of acute seizures are summarized. Methods: Please refer to the listed publications for methods. Results: (a) In 14 rats for which optical CSD was induced by seizures, the CSD showed characteristic triphasic responses, which spread symmetrically in all directions, at a rate of ∼3.5 mm/min. The optical CSD showed an intricate back‐and‐forth reciprocal interaction, with the seizure activity at the interface of CSD and seizures. (b) In eight rats, before epileptiform discharges were detectable on EEG, the region near penicillin application increased light reflectance (∼10% changes from the baseline). The surrounding region showed decreased light reflectance (∼5% changes from the baseline). During seizure induction, the central region gradually decreased, and the reversal of the light reflectance changes coincided with the onset of spikes. (c) In 10 rats, OIS imaging at 610 nm, which detected deoxyhemoglobin concentration changes, was sensitive to the early detection of seizures. Imaging at 610 nm does not follow spike‐to‐spike fluctuation well, but instead shows a tonic response correlating with the overall seizure intensity. This response dissociates from seizure intensity when seizures intensify. Imaging at 850 nm, known to correlate with neuronal activation, shows “optical spikes” that correlate well with single spikes on EEG. Conclusions: (a) Seizure‐induced CSD showed reciprocal inhibitory effects on seizure activity. (b) OIS imaging at 610 nm detected optical changes in the preictal phase during seizure induction, and reversal of light reflectance could define seizure onset. (c) Imaging at 610 nm represented overall seizure intensity and, at 850 nm, correlated well with single spikes. (Supported by NINDS grant K08 NS42708.) *Massimo Avoli, *Giuseppe Biagini, *Giovanna D'Arcangelo, *Margherita D'Antuono, and *Virginia Tancredi ( *MNI/McGill University, Montreal, Quebec, Canada ). Mesial temporal lobe epilepsy (MTLE) patients present with seizures involving the limbic system and with a pattern of brain damage characterized by neuronal loss in CA1/CA3 areas, dentate hilus, and entorhinal cortex (EC), layer III (Houser CR. Adv Neurol 1999;79:743–61). Similar findings are seen in laboratory animals following pilocarpine injection (Turski WA, et al. Behav Brain Res 1983;9:315–35). This procedure induces an initial convulsive response, which is followed within 2–3 weeks by recurrent seizures. Limbic network hyperexcitability in MTLE and in animal models results from seizure‐induced brain damage leading to (a) synaptic reorganization (Cavazos JE, et al. J Neurosci 1991;11:2795–803; Houser CR. Adv Neurol 1999;79:743–61) and (b) changes in GABA receptor–mediated inhibition (Buhl EH, et al. Science 1996;271:369–7; Doherty J, Dingledine R. J Neurosci 2001;21:2048–57. However, it is unclear how these changes lead to a chronic epileptic condition. CA3‐driven interictal activity induced in normal brain tissue by epileptogenic stimuli inhibits the EC from generating ictal discharges (Barbarosie M, Avoli M. J Neurosci 1997;17:9308–14), suggesting that CA3 damage causes a decrease of hippocampal output activity that would release EC ictogenesis and establish a chronic epileptic condition. Accordingly, slices obtained from pilocarpine‐treated epileptic mice respond to 4‐aminopyridine (4AP) application by generating (a) CA3‐driven interictal activity that is less frequent than in nonepileptic control (NEC) tissue, and (b) ictal discharges that do not disappear over time and propagate to the CA1‐subiculum via the temporoammonic path (D'Antuono M, et al. J Neurophysiol 2002;87:634–9). From these findings, we predicted that limbic seizures result from EC–subiculum interactions. Using brain slices obtained from pilocarpine‐treated, epileptic rats, we found that decreased CA3 output function, along with reverberation between EC and subiculum networks, lead to in vitro epileptogenesis. First, intense activation of EC and subiculum was identified with intrinsic optical signal (IOS) recordings in pilocarpine‐treated, but not in NEC slices. Second, using field potential recordings during 4AP application, we established that CA3‐driven interictal activity occurs at lower frequency in pilocarpine‐treated slices and that disconnection of the EC from the subiculum attenuates 4AP‐induced ictal discharges in pilocarpine‐treated, but not in NEC slices. Third, the distribution of FosB/FosB‐related proteins in epileptic tissue demonstrated distinct patterns overlapping those seen with IOS recordings, with the highest intensity in layer III of the lateral EC. In conclusion, our data show that hippocampal damage in epileptic rats, and perhaps in MTLE patients, hampers the ability of CA3 output activity to control ictogenesis in the EC. Such a process is reinforced by interactions between subiculum and EC networks. *Ricardo Mario Arida, *Fulvio Alexandre Scorza, *Reinaldo de Amorin Carvalho, and *Esper Abrão Cavalheiro ( *Neurologia Experimental‐Escola Paulista de Medicina, São Paulo, Brazil ). The potential interest of Proechimys guyannensis (PG), a spiny rat living in the Amazonian region, as an animal model of anticonvulsant mechanisms prompted the investigation of the susceptibility of PG to different epileptogenic paradigms. The findings pointed out a remarkable resistance of these animals to different models of experimental epilepsy. (1) Amygdala kindling development. Proechimys animals demonstrated a striking resistance to reaching stage 5 of kindling. Of 43 Proechimys rats submitted to the kindling process, only three animals reached stage 5. Of 40 animals that did not reach the kindled state, 16 did not get beyond stage 1, 15 did not get beyond stage 2, seven did not get beyond stage 3, and three did not get beyond stage 4. Amygdala electrical stimulations were followed by very long afterdischarges, mainly in stages 1–4. (2) Intrahippocampal kainic acid (KA). A remarkable sensibility to intrahippocampal KA was noticed in PG. One‐tenth of the KA dose usually used in Wistar rats elicited self‐sustained electrographic status epileptus (SE) in PG animals, which lasted for >48 h with increased mortality rate. On the other hand, none of the surviving animals presented spontaneous seizures in the long‐term observation period (up to 120 days). Neuropathological examinations of the hippocampus of Proechimys animals after KA injection showed a complete neuronal destruction at the injected hippocampal formation, more pronounced in CA1/CA3 areas, and with less marked changes in the contralateral hippocampus. (3) Pilocarpine. Pilocarpine (350–380 mg/kg, doses regularly used in Wistar rats), when administered to PG, induced severe tonic seizures followed by death of all animals. A dose slightly lower (300 mg/kg) than those previously mentioned was able to induce repetitive electrographic and behavioral seizures that culminated in SE 20–30

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