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Laboratory of Neurophysiology, Faculty of Medicine, Laval University, Quebec, G1K 7P4, Canada
Submitted 30 May 2003; accepted in final form 22 January 2004
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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; Niedermeyer 1999a,1999b), and different neuronal substrates contribute to the generation of various electrographic paroxysms. Studies on experimental animals show that some electrical seizures are generated intracortically, even in the absence of the thalamus (Steriade and Contreras 1998). These seizures are characterized by spike-wave (SW) or spike-wave/polyspike-wave (SW/PSW) complexes of 1.5–3 Hz, intermingled with episodes of fast runs at 
10–20 Hz (Neckelmann et al. 1998; Steriade and Contreras 1998; Steriade et al. 1998b; Timofeev et al. 1998). Generally, these seizures evolve from the cortically generated slow oscillation (Steriade and Contreras 1995; Steriade et al. 1998b) that might be shaped by the thalamus (Hughes et al. 2002). The electrographic pattern of these seizures as well as their occurrence during slow-wave sleep resemble the clinical Lennox-Gastaut syndrome of humans (Halasz 1991; Kotagal 1995; Niedermeyer 1999a,1999b).
The treatment of these seizures is usually based on the use of antiepileptic drugs that limit sustained repetitive firing via use-dependent blockage of voltage-gated Na+ channels, facilitate the inhibitory action of GABA, combine the preceding actions (Brodie and French 2000; Brodie and Kwan 2001), or act simultaneously on persistent Na+ current, Ca2+-activated K+ current and possibly low-threshold Ca2+ current (Crunelli and Leresche 2002). However, despite antiepileptic drug treatment, more than one-third of patients continue to display seizures (Kwan and Brodie 2000). This suggests that other abnormalities than impaired inhibition and enhanced activity of Na+ currents may be involved in the generation of such paroxysmal activities.
The cellular mechanisms underlying the generation of electrical seizures were explored since the 1960s (Matsumoto and Ajmone-Marsan 1964a,1964b). Despite significant efforts, we still lack data to account for all neuronal mechanisms that are involved in paroxysmal activities. Initial studies suggested that the paroxysmal depolarizing shift (PDS) consists of a giant excitatory postsynaptic potential (EPSP) (Johnston and Brown 1981) enhanced by activation of voltage-regulated intrinsic currents (de Curtis et al. 1999; Dichter and Ayala 1987; Prince and Connors 1984; Westbrook and Lothman 1983; Wong and Prince 1978). These and other similar studies were performed in the presence of GABAA receptor antagonists. Some experimental data point out that synaptic inhibition remains functional in many forms of paroxysmal activities (Davenport et al. 1990; Esclapez et al. 1997; Higashima 1988; Prince and Jacobs 1998; Timofeev et al. 2002b; Traub et al. 1996), and more recent studies suggest that GABAergic activities in the epileptic foci depolarize postsynaptic neurons (Cohen et al. 2002; Timofeev et al. 2002b).
In conjunction with our recent studies (Bazhenov et al. 2004; Timofeev et al. 2002a,2002b), we address here the question: what ionic conductances mediate the depolarizing and hyperpolarizing components of electrographic seizures in which inhibition was not impaired via application of GABA blockers? We provide evidence that, besides synaptic drives, the voltage-gated Na+ and probably the high-threshold Ca2+ conductances contribute to the generation of the depolarizing components of seizures, while Ca2+-activated K+ [gK(Ca)] and other K+ conductances mediate the hyperpolarizing components of cortically generated electrographic seizures. These data may create a new avenue for the development of antiepileptic drugs.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Field potential recordings and stimulation were obtained by using bipolar coaxial macroelectrodes inserted into the cortex. The outer pole of the electrode was placed at the cortical surface or 0.1 mm deeper, whereas the inner pole was placed at 0.8–1 mm in the cortical depth. After ketamine-xylazine anesthesia, 30% of cats (n = 28) displayed spontaneously occurring electrographic seizures consisting of SW/PSW complexes at 1.5–3 Hz, often associated with fast runs at 10–15 Hz. The reason(s) accounting for a relatively high incidence of spontaneous seizures, in addition to the propensity to paroxysms under ketamine anesthesia, are discussed elsewhere (Steriade et al. 1998b).
Intracellular recordings from cortical neurons were obtained with sharp glass micropipettes having resistance of 30–80 M
. We aimed to obtain dual intracellular recordings from pairs of closely located neurons (lateral distance <0.5 mm; see Table 1). In all cases, one of the electrodes was filled with a solution of 2.5–3.0 M K+ acetate (KAc), while another electrode was filled either with KAc, or 2.0 M Cs+ acetate, or KAc containing 50 mM of 1,2-bis (2-aminophenoxy) etane-N,N,N',N'-tetraacetic acid (BAPTA), or 50 mM of N-(2,6-dimethyl-phenylcarbamoylmetyl)-triethylammonium bromid (QX-314). All drugs were purchased from Sigma. In some experiments, 2% of neurobiotine (Vector, Canada) was added to pipettes. A high-impedance amplifier (band-pass, 10 kHz) with an active bridge circuitry was used to record and inject current into the neurons. Before the recording session, 3- to 5-nA current pulses were passed through all the pipettes to test the correctness of balance of each pipette at a wide range of injected currents. The signals were recorded on a tape with band-pass of 
0–9 kHz and digitized at 10–20 kHz for off-line computer analysis. In the latest experiments data were digitalized on-line and recorded on Vision (Nicolet, WI) at 20 kHz.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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We aimed to obtain dual simultaneous intracellular recordings from pairs of closely located neurons (lateral distance: <0.5 mm) and the actual distance measured from intracellularly stained pairs of neurons (n = 15) was <0.3 mm (Fig. 1). We recorded intracellular activities from 391 cortical neurons located at depths between 300 and 1,800 µm (micromanipulator reading). In paired recordings, the depth difference between two neurons did not exceeded 200 µm. Of the neurons tested, 270 were recorded with pipettes filled with KAc (2.5 M). Other neurons were recorded with pipettes containing different substances (Table 1). All neurons were formally identified by electrophysiological criteria as regular-spiking (RS), intrinsically bursting (IB), fast-rhythmic-bursting (FRB), and fast-spiking (FS) (Connors and Gutnick 1990; Gray and McCormick 1996; Steriade et al. 1998b).
Control experiments
Dual intracellular recordings during seizures from pairs of neurons located in different cortical areas disclosed synchronous behavior at a large scale, but close examination showed that there were significant time delays in the onset of PDSs and differences in amplitudes (Neckelmann et al. 1998). At variance, recordings from closely located (<0.5 mm) neurons indicated that the excursion of intracellular traces of simultaneously recorded neurons during paroxysmal activities was almost identical (no current injection was needed to line up the traces) and, at any given moment of time, the difference in voltage of neurons that belonged to the same electrophysiological class did not usually exceed 3 mV (Fig. 1). The exception to this rule concerned only action potentials, spike-related prepotentials, and spike afterhyperpolarizations (AHPs). Those components contributed to the histogram bins of 5–6 mV (Fig. 1). During periods outside the seizures, the membrane potential in the active periods was similar too, but the difference in the membrane potential during the silent phases of oscillations, which correspond to depth-positive EEG waves, could reach 
10 mV (not shown). Because most of paired recordings were obtained from RS neurons that represent the majority of neocortical neurons, the analysis of actions exerted by intracellular drugs on different components of intracellular activities during seizures was mainly performed on pairs of RS neurons.
Hyperpolarizing components of seizures
Two types of seizure-related hyperpolarizing potentials were considered in the present study: relatively short-lasting hyperpolarizations (200–300 ms), which occurred between two consecutive PDSs, and long-lasting hyperpolarizations at the end of seizures. The input resistance of neurons during both these components was lower than during the preseizure epoch (Neckelmann et al. 2000; Timofeev et al. 2002b), suggesting the strong activation of some currents during the seizure-related hyperpolarizations as well as during the postictal depression. These hyperpolarizations were not Cl–-dependent inhibitory postsynaptic potentials (IPSPs) because they were not affected by intracellular Cl– infusion and were not associated with a simultaneous firing of FS neurons (Timofeev et al. 2002b). Thus we hypothesized that K+ currents mediated these hyperpolarizing potentials.
To test this hypothesis, we performed intracellular recordings with Cs+-containing pipettes (2 M), which blocks intracellularly most K+ currents (Hille 2001). Intracellular recordings with Cs+-containing pipettes during seizures had a profound influence on intracellular activities. One to 2 min after impalement, during the pause between successive electrographic seizures, the neuron revealed depolarizing plateau potentials (Fig. 2, green); however, during the seizure, these large depolarizing potentials were truncated by PDSs. Two to 3 min after beginning of intracellular recordings with Cs+-containing pipettes, during the postictal depression, the membrane potential of neurons was depolarized and remained in the range between –10 and –30 mV. Under these conditions, the intracellular manifestation of seizure appeared to be reversed, that is, the PDSs were hyperpolarizing (Fig. 2, blue; see arrow). The membrane potential during PDSs reached the same value or only a few millivolts more depolarized values than the membrane potential of the same neuron during PDSs immediately after impalement. EEG "waves" of spike-wave complexes, which are normally associated with hyperpolarizing potentials, were accompanied by depolarizing events, or the membrane potential did not change significantly between consecutive PDSs. This pattern did not change over tens of minutes of recordings.
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), this effect was saturated after 30–40 min of stable recordings (n = 7, not shown). These data indicate that IK(Ca) contributes to the generation of hyperpolarizing potentials during seizures. The fact that the time course of effects exerted by intracellular BAPTA on spike AHP and on EEG wave-related hyperpolarizations was different might suggest, but not demonstrate directly, that the subtypes of Ca2+-dependent K+ channels, which mediate these two potentials, were either different (Sah and Louise Faber 2002; Schwindt et al. 1988) or located in different compartments of the neuron.
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The depolarizing components of seizures under scrutiny are represented by PDSs during SW/PSW complexes and the steady depolarization of cortical neurons during the fast runs. Because neurons achieve a significant depolarization during both these components, often higher than the firing threshold, we hypothesized that in addition to synaptic drive (Johnston and Brown 1981) some high-threshold voltage activated currents may contribute to the generation of PDS. In a previous study, we have shown that PDSs increase their duration on intracellular injection of steady depolarizing current (Timofeev et al. 2002b). This suggests that high-threshold Ca2+ currents and the persistent sodium Na+ current [INa(p)] could contribute to those depolarizations because these currents are activated at depolarized voltages. In vivo intracellular tools are rather limited, and we were not able to use intracellular blockers of Ca2+ currents. However, our data shown in Figs. 4– 6, in which BAPTA (a Ca2+ chelator) was used, indirectly suggest the contribution of Ca2+ currents in the generation of PDSs. Indeed, IK(Ca) significantly contributes to neuronal hyperpolarization during the EEG wave component, thus suggesting that substantial amounts of Ca2+ enter the neurons during the PDSs and thus Ca2+ currents may be implicated in the generation of PDSs.
To study whether or not INa(p) contributes to the generation of PDSs, we performed intracellular recordings with pipettes filled with 50 mM of QX-314, an intracellular blocker of voltage-dependent Na+ currents. These recordings revealed that voltage-dependent Na+ currents significantly contribute to the generation of both PDSs (Fig. 7) and fast runs at 10 Hz (Fig. 8). The earliest effects of intracellularly diffused QX-314 were seen in 1–2 min after impalement and consisted of small reduction in the maximal depolarization achieved by the neuron during the PDS. At that time, the fast spikes generated by the transient Na+ current (the amplitude, rise time, and firing threshold) were not yet affected by QX-314. The maximal effect of QX-314 was achieved after 5–8 min from the beginning of recording and consisted of complete or partial abolition of Na+ spikes and significant reduction of PDSs' amplitudes. The effects of QX-314 on intracellular potential were voltage dependent. At the beginning of a seizure, the maximal depolarization reached by control neurons (no QX-314 added) was from –50 to –60 mV. The mean difference in membrane potential between control neurons and simultaneously recorded neurons loaded with QX-314 was 3.5 mV (Fig. 7B). As the seizure progressed, the maximal depolarization of control neurons during PDSs became between –40 and –35 mV, and the difference between control neurons and QX-314-containing neurons reached 20–25 mV.
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), we suggested that each paroxysmal cycle is triggered by 20% of cortical neurons that express hyperpolarization-activated depolarizing current (Ih). In the other 80% of neurons, the onset of PDS is likely driven by synaptic conductances. To study the role of INa(p) in the enhancement of the initial synaptic depolarization, we performed wave-triggered averages where the maximum of EEG depth-negativity was taken as zero (Fig. 8). These data showed that not only the amplitude, but also the slope, of PDS was slower in neurons recorded with pipettes filled with QX-314. This strongly suggests that INa(p) significantly contributes in boosting the amplitude, slope, and the maintenance of depolarization reached during the PDS. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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Some methodological issues
Each seizure is unique, and each neuron is different as it has a given number of synapses, located at various compartments, and a unique set of intrinsic currents. The relative contributions of all synaptic and intrinsic currents experienced by cortical neurons during an electrical seizure at a given neocortical site are different. We stained some of the recorded neurons, and we were able to reveal during subsequent morphological analysis that the lateral distance between these neurons was <0.3 mm (see Fig. 1). Given such close distance between recorded neurons, similar to studies in other forebrain structures (Stern et al. 1998), the large-scale synchrony in fluctuations of the membrane potential was similar but on a smaller scale, and during normal brain oscillations the membrane potential of neurons was different. However, during seizures, the membrane potential of closely located recorded neurons was virtually identical (Fig. 1). Thus to evaluate the role of possible currents contributing to the generation of different components of seizures, we used simultaneous dual intracellular recordings in which one of the pipettes was filled with a substance to block some currents. This method allowed us to compare the effects of different intracellular drugs with control recordings during the same seizure. Most of the drugs used in the present study had a fast action and, after stabilization of recording, the drug already affected intracellular activities. In those instances in which the quality of recordings was good even immediately after impalement, we were able to study the activity of the same neuron at the beginning of recording as well as several minutes later compared with the activity of a nearby, simultaneously recorded neuron (Fig. 5). In such conditions, the intracellular activities of neurons recorded with pipettes filled with KAc and with pipettes containing other solutions were very similar at the beginning of recordings, and differences between recordings with two different pipettes (as described in RESULTS) became apparent after several minutes. Thus we are confident that the reported results represent the effects of intracellularly applied drugs on neuronal activities.
Another issue concerns the specificity and the spatial extent of the intracellular drugs. The intracellular Cs+ used in this study blocks most of K+ conductances (Hille 2001). As such, the major outward currents were turned off; the neuron became depolarized, and in this state, the high-threshold currents were nonspecifically activated. QX-314 is usually used to block the voltage-gated Na+ currents and G-protein-dependent K+ currents (Andrade 1991; Andreasen and Hablitz 1993; Benardo et al. 1982; Wilson and Kawaguchi 1996), and it also partially blocks high-threshold Ca2+ currents (Talbot and Sayer 1996). However, in our experiments, the QX-314 did not affect the hyperpolarizing phases of the seizures, suggesting that most of the observed effects were initiated by changes in voltage-gated Na+ conductances. The block of INa(p) in the perisomatic region significantly decreased the amplitude of PDSs. We cannot exclude that blockage of Na+ conductances did not affect high-hreshold Ca2+ currents because after blockage of Na+ depolarizing influences, the membrane was not sufficiently depolarized to drive Ca2+ currents.
All in all, our data suggest which conductances contribute to the generation of different components of seizures but cannot indicate the extent of the action. To compensate for this incompleteness of measurements, we used a computational modeling approach that is fully described in the companion paper (Bazhenov et al. 2004).
Sequence of events leading to the seizure generation, maintenance, and termination
Different seizures have different origins. It has been shown that the slow sleep oscillation and cortically generated seizures share many similarities as, during both slow oscillation and seizures, the field EEG potentials reveal periodic positive and negative waves and cortical neurons are depolarized during the EEG depth-negativity and hyperpolarized during the EEG depth-positivity (Steriade et al. 1998b). Due to spontaneous variations in the degree of membrane polarization, the depolarizing component of the cortical slow oscillation may induce higher than usual neuronal firing (see Fig. 1 in Bazhenov et al. 2004). The increased firing rapidly increases the local [K+]o, which creates conditions for neuronal swelling leading to tighter synchronization between neurons (Andrew and MacVicar 1994; Dietzel et al. 1980; Grenier et al. 2003a). Consequently, in the focus of seizure generation many cortical neurons start to fire simultaneously at frequencies 100 Hz, generating the initial PDS (Grenier et al. 2003b). Another possible mechanism of seizure initiation might be based on advanced firing of IB neurons. In in vitro models of epileptiform activities, those bursts preceded the onset of field paroxysmal discharges (Chagnac-Amitai and Connors 1989; Jensen and Yaari 1997; Sanabria et al. 2001). Although this possibility exists, we cannot support it with our data because the firing of none of >100 IB neurons recorded in the present and our previous in vivo studies (not shown) did not anticipate the field potential paroxysmal spikes and the relative number of IB neurons is very low (4%) in behaving animals (Steriade et al. 2001), whereas many of them display spontaneous seizures.
What are the main elements that contribute to PDS generation? In the majority of neurons, the initial depolarization during PDS is driven by EPSPs arising in neighboring or more distant cortical neurons. Studies in bicuculline-treated slices suggested that the PDS is a giant EPSP (Johnston and Brown 1981). More recent data suggest, however, that synaptic inhibition remains functional in most forms of paroxysmal activities (Davenport et al. 1990; Esclapez et al. 1997; Higashima 1988; Prince and Jacobs 1998; Traub et al. 1996) and significantly contribute to PDS generation because of the depolarizing driving force in conditions of high [K+]o (Timofeev et al. 2002b). So far, the enhancement of PDS by activation of voltage-regulated intrinsic currents was only shown in vitro (de Curtis et al. 1999; Dichter and Ayala 1987; Prince and Connors 1984; Westbrook and Lothman 1983; Wong and Prince 1978). In the present study, the effects exerted by QX-314 support the idea that INa(p) (Crill 1996; Stafstrom et al. 1982) contributes to the generation of PDSs in vivo (Figs. 7 and 8). The fact that intracellularly infused BAPTA affected both de- and hyperpolarizing components of seizure indicates that significant quantities of Ca2+ entered the neurons during the PDS. An important contribution of N-methyl-D-aspartate (NMDA)-dependent Ca2+ contribution is unlikely because our experiments were done under ketamine-xylazine anesthesia, and ketamine at anesthetic doses blocks NMDA-dependent synaptic events (MacDonald et al. 1991). Our data do not allow the exact estimation of the ratio of different depolarizing factors because synaptic depolarizing influences activate intrinsic Na+ and Ca2+ conductances that boost each other. However, given the fact that INa(p) is activated at voltages that are by 10 mV lower that the firing threshold of neurons (Crill 1996), we expect that the initial intrinsic drive depends on this ionic current. An interaction of somatic firing with dendritic depolarization (Stuart and Hausser 2001) may further boost paroxysmal depolarization.
The seizure's hyperpolarizations and/or postictal depression (related to the EEG waves) were strongly dependent on Cs+-sensitive K+ currents. Within 1–2 min after impalement, all RS neurons revealed depolarizing potentials during paroxysmal activities and were depolarized by about –20 mV during the pause between successive epileptiform events (Fig. 2), thus pointing to a dominant role of K+ currents in the generation of seizure-related hyperpolarizing potentials. However, such a strong depolarization was probably achieved by activation of Ca2+ currents, in the absence of the majority of hyperpolarizing K+ currents, rather than by the simple absence of hyperpolarizing influences. This conclusion is also based on the fact that, during seizures, when the time between consecutive PDSs was short and there was no depolarizing drive to generate depolarizing plateau potentials, the membrane potential remained unchanged (Fig. 2). Intracellular BAPTA significantly decreased hyperpolarizing potentials during the seizure (Fig. 4), but its effect was much less strong, compared with that of intracellularly infused Cs+, suggesting that other K+ currents contributed to the generation of hyperpolarizing potentials. One of the most likely candidates is IK(Na) (Schwindt et al. 1989). Indeed, a significant amount of Na+ enters cortical neurons during the PDSs and may thus activate this current.
The putative role of GABAB-receptor-mediated IPSPs in the generation of seizure-related hyperpolarizations, previously proposed in modeling studies (Destexhe 1998), is unlikely because long-lasting recordings with pipettes containing QX-314, a potent intracellular blocker of GABAB IPSPs (Nathan et al. 1990) did not affect the generation of seizure-related hyperpolarizing potentials (Figs. 7 and 8). Thus we conclude that IK(Ca) and a "leak" current are major contributors for the generation of seizure-related hyperpolarizing potentials. When a significant hyperpolarization occurred, in conditions of increased [K+]o, the Ih depolarized a part of cortical neurons to firing threshold, which led to the generation of the next paroxysmal cycle (Chen et al. 2001; Timofeev et al. 2002a).
During the seizure, the long-range synchronization between remote sites of recordings increases (Steriade and Amzica 1994; Topolnik et al. 2003), leading to increased maximal depolarization, which is achieved by neurons that are involved in PDSs toward the end of the seizure (Steriade et al. 1998a). The increase in the depolarization is associated with increased intracellular concentrations of Na+ and Ca2+, which in turn activate IK(Ca) and IK(Na) currents, resulting in an increase in the maximal hyperpolarization achieved by neurons (Steriade et al. 1998a). When this hyperpolarizing potential overwhelms the depolarization induced by Ih, the seizure is terminated.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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Address reprint requests and other correspondence to: I. Timofeev (E-mail: Igor.Timofeev{at}phs.ulaval.ca).
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REFERENCES |
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