ELECTROPHYSIOLOGIC CHANGES IN THE LATERAL AND BASAL AMYGDALOID NUCLEI IN TEMPORAL LOBE EPILEPSY: AN IN VITRO STUDY IN EPILEPTIC RATS M. NIITTYKOSKI, a J. NISSINEN, a M. PENTTONEN b AND A. PITKA ¨ NEN a,c * a Epilepsy Research Laboratory, Department of Neurobiology, A.I. Vir- tanen Institute for Molecular Sciences, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland b Cognitive Neurobiology Laboratory, Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland c Department of Neurology, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Finland Abstract—The functional consequences of neuronal loss during epileptogenesis in the lateral and basal amygdaloid nuclei are poorly understood. The present study tested the hypothesis that electrical responsiveness varies in different amygdaloid nuclei in the chronically epileptic amygdala. Further, we examined the amygdaloid region most prone to seizure initiation. Epileptogen- esis was triggered in 20 rats by inducing status epilepticus (SE) with electrical stimulation of the lateral nucleus of the amygdala. Electrode-implanted non-stimulated rats served as controls. The occurrence and duration of spontaneous seizures were monitored with video-electroencephalography (EEG) at 8 –9 weeks after SE. Thereafter, animals were killed and extracellular recordings were made from slices of both amygdalas. In the lateral nucleus of epileptic animals, the frequency of spontaneous responses was reduced compared with controls (P<0.05). The amplitudes of evoked ﬁeld responses were reduced (P<0.01), whereas paired pulse (PP) facilitation was enhanced (P<0.05). In the basal nucleus of the epileptic animals, PP facilitation was enhanced (P<0.05) and sensitivity to 4-aminopyridine (4-AP)-induced epileptiform activity was increased compared with controls (P<0.05). In the epileptic animals, the basal nucleus was also more sensitive than the lateral nucleus to 4-AP-induced epileptiform activity (P<0.05). Correlation analysis indicated that longer SE duration was associated with longer half widths (P0.001) and smaller slopes (P<0.05) of evoked responses as well as with attenuated PP facilitation (P<0.01). Moreover, a higher frequency of spontaneous seizures was associated with longer half widths (P<0.05) and smaller slopes (P<0.05) of evoked responses as well as with enhanced PP facilitation (P<0.05). These data suggest that there is a reduced release of glutamate and reduced inhibition in the lateral and basal amygdaloid nuclei in epileptic animals. Further, the basal nucleus is more prone to epileptic activity than the lateral nucleus. Finally, the severity of SE and spontaneous seizures in vivo is associated with electrophysiologic alterations in vitro. © 2004 IBRO. Pub- lished by Elsevier Ltd. All rights reserved. Key words: 4-aminopyridine, amygdala, epileptiform activity, extracellular, slice, spontaneous seizures. Recordings with intracerebral electrodes in patients with drug-refractory temporal lobe epilepsy (TLE) indicate that the amygdala is involved in the initiation of seizures up to 68% (Quesney, 1986). Further, single unit recordings in patients with the seizure focus in the amygdala and/or anterior hippocampus demonstrated a prolonged burst du- ration in amygdaloid neurons during the interictal period (Isokawa-Akesson et al., 1987). Consistent with the altered electrophysiology, magnetic resonance imaging studies revealed that the amygdala is damaged in approximately 25% of TLE patients (for review, see Pitka ¨ nen et al., 1998). Based on histologic studies, damage in the human amyg- dala is most pronounced in the ventral aspects of the lateral nucleus as well as in the parvicellular division of the basal nucleus (for review, see Pitka ¨nen et al., 1998). Im- portantly, there is a similar distribution of damage in animal models in which spontaneous seizures can develop as a consequence of status epilepticus (SE; Tuunanen et al., 1996; Nissinen et al., 2000). There are few data, however, regarding the association of cellular damage with in- creased amygdaloid responsiveness in epilepsy. Such data are important for our understanding of seizure initia- tion in the amygdala and the spread in temporal lobe circuits, as well as for identiﬁcation of anatomic targets for novel treatments. One nucleus-speciﬁc alteration in the amygdala is in- creased excitability in the basal nucleus. For example, Mangan et al. (2000) reported that the width of excitatory postsynaptic potentials and maximum number of evoked action potentials were increased in the basal nucleus of spontaneously seizing animals. Further, the stimulus inten- sity required to evoke action potentials was decreased. Previous studies also demonstrated either a reduction or total absence of spontaneous and evoked inhibitory poten- tials in the basal nucleus in epileptic rats (Smith and Dudek, 1997; Mangan et al., 2000). Consistent with the electrophysiology, studies with 14 C-2-deoxyglucose auto- radiography and c-Fos immunochemistry indicate that the basal nucleus is one of the brain regions with the largest metabolic increase during SE (White and Price, 1993a; Pereira de Vasconcelos et al., 1999). Further, inactivation of the basal nucleus with lidocaine stops electrically-in- duced SE, supporting the idea that the basal nucleus of the amygdala is a critical site for the generation of SE (White and Price, 1993b). Other amygdaloid regions, however, *Correspondence to: A. Pitka ¨ nen, A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. Tel: +358-17-163296; fax: +358-17-163025. E-mail address: asla.pitkanen@uku.ﬁ. Abbreviations: aCSF, artiﬁcial cerebrospinal ﬂuid; EEG, electroencephalography; HAFD, high-amplitude and frequency discharge; NMDA, N-methyl-D-aspartate; PP, paired pulse; SE, status epilepticus; TLE, temporal lobe epilepsy; 4-AP, 4-aminopyridine. Neuroscience 124 (2004) 269 –281 0306-4522/04$30.00+0.00 © 2004 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2003.11.027 269