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FIGURE 3 A: Ictal-like discharges recorded in low [Ca2+]o in the CA1 region. Traces are shown at different time scales (expanded time frame in middle trace, slower time frame below). (Adapted from Konnerth et al., 1986.) B: Spontaneous epileptiform discharges recorded in Mg2+-free artificial cerebrospinal fluid (aCSF). These discharges were modulated by application of the N-methyl-D-aspartate (NMDA) receptor antagonist APV. (Adapted from Mody et al., 1987.) C: Spontaneous ictal-like discharge recorded in the CA1 region in toto, in Mg2+-free aCSF. (Adapted from Quilichini et al., 2002.) D: Spontaneous ictal-like discharges recorded in the CA1 region in slices exposed to elevated extracellular [K+]. Different portions of the discharge are displayed at different time scales. (Adapted from Traynelis and Dingledine, 1988.)

FIGURE 3 A: Ictal-like discharges recorded in low [Ca2+]o in the CA1 region. Traces are shown at different time scales (expanded time frame in middle trace, slower time frame below). (Adapted from Konnerth et al., 1986.) B: Spontaneous epileptiform discharges recorded in Mg2+-free artificial cerebrospinal fluid (aCSF). These discharges were modulated by application of the N-methyl-D-aspartate (NMDA) receptor antagonist APV. (Adapted from Mody et al., 1987.) C: Spontaneous ictal-like discharge recorded in the CA1 region in toto, in Mg2+-free aCSF. (Adapted from Quilichini et al., 2002.) D: Spontaneous ictal-like discharges recorded in the CA1 region in slices exposed to elevated extracellular [K+]. Different portions of the discharge are displayed at different time scales. (Adapted from Traynelis and Dingledine, 1988.)

epileptiform activity and the role of interneurons in those discharges (Perez Velazquez, 2003). Interestingly, although not present in acute hippocampal slices, ictal-like discharges can be recorded in Mg2+-free aCSF in the in toto immature hippocampal preparation (Figure 3C) (Quilichini et al., 2002). This preparation is useful for testing antiepileptic drugs (Quilichini et al., 2003). The electrographical signature of the discharge is very similar to that recorded in patients.

complex network questions such as the mechanisms of fast ripples at seizure onset (Dzhala and Staley, 2004) and the transition from interictal to ictal activity (Dzhala & Staley, 2003b). This model is particularly useful because it causes an elevation of the general excitability of all neural networks; it is noteworthy that elevations of [K+]o comparable in magnitude to the K+ changes imposed on hippocampal slices occur during seizures in vivo (Fisher and Alger, 1984; Lothman, 1976; Moody, 1974).

Elevated K+ Model of Epilepsy

Bathing slices with 8.5 mM K+ results in the occurrence of spontaneous tonic-clonic discharges (Figure 3D) (Traynelis and Dingledine, 1988). Under these conditions, it is possible to investigate the role of GABAergic neurotransmission (Dzhala and Staley, 2003a), the behavior of the different hippocampal cell types (McBain, 1994), and

Chronic Models of Epilepsy

Hippocampal slices can be obtained from chronic animal models of epilepsy. The technical advantages of the slice to investigate detailed cellular and synaptic phenomena has been particularly important in studying models of TLE and epileptogenesis, such as the kindling, kainate, and pilo-carpine models. Two epochs following an epileptogenic event or stimulus have been investigated: the chronic phase of epilepsy, during which the animals display spontaneous recurrent seizures (epilepsy), and the latent period, the interval between the initial insult and the first spontaneous seizure (epileptogenesis). The hippocampus undergoes considerable modifications during epileptogenesis as well as during the chronic phase. In designing experiments focused on these issues, the investigator must consider this "reactive plasticity" to be a dynamic process and assume that results may vary, depending on what parameters are measured and when.

An obvious advantage of studying hippocampal slices from chronic animal models (as opposed to studying epilep-tiform phenomena in "normal" tissue) is the fact that these animals are epileptic. This fact allows the investigator to analyze parameters that are correlated with the epileptic state or may be causally related to ictogenesis. Unfortunately, as suggested already, interictal-like or ictal-like discharges have not been reported to occur—under physiologic conditions—in slices obtained from epileptic animals. However, slices from the ventral hippocampus, in which spontaneous waves can be recorded, remain to be tested (Colgin et al., 2004; Kubota et al., 2003). Further, the epilep-togenic challenges described in the previous section (e.g., GABAa receptor blockade, high K+, low Mg2+, etc.) can be used to unveil the epileptic propensity of slices from chronic models. Comparing the pattern and properties of interictal-like or ictal-like activity between control and epileptic slices may reveal important information about functional reorganizations (e.g., sprouting of excitatory axons) that take place during epileptogenesis or during the chronic phase of epilepsy (Cronin et al., 1992; Hardison et al., 2000; Lynch and Sutula, 2000; Patrylo and Dudek, 1998; Patrylo et al., 1999; Wuarin and Dudek, 1996). Another use of these slices is to investigate the details of modifications of hippocampal circuitry associated with the epileptic state. Questions are usually related to the fate of glutamatergic and GABAergic pathways as well as of ionic channels. Many studies are based on a multidisciplinary approach that combines elec-trophysiology, functional morphology, or molecular biology (Bernard et al., 2004; Brooks-Kayal et al., 1998; Buhl et al., 1996; Chen et al., 2001, 2003; Cossart et al., 2001; Esclapez et al., 1997, 1999; Nusser et al., 1998; Ratzliff et al., 2004; Scharfman et al., 2000; Su et al., 2002).

As indicated already, the main difficulty in applying slice approaches to studying chronic animal models lies in interpretation of the data. Seizures in temporal lobe epilepsy usually involve several limibic regions. The exact anatomic location(s) of seizure initiation and of the propagation patterns remain unknown, and there is high variability from one patient to another. Thus it is still unclear where the investigator should look in the hippocampal slice for TLE-related abnormalities. It is perhaps more useful to focus on epilepsy-induced plasticity and to use the slice preparation to eluci date the details of these changes. Even here, however, much of the connectivity is lost in the slice preparation—even from normal animals—and so correlating slice abnormalities with epilepsy-related pathology may be hazardous. Nevertheless using the hippocampal slice preparation to identify parameters in which alterations could be potentially "preepileptic" may provide new therapeutic targets (Bernard et al., 2004; Su et al., 2002).

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