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Neural Engineering Center, Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106
Submitted 13 March 2003; accepted in final form 10 June 2003
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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). However, since the 1980s, a nonsynaptic epilepsy model has been established in hippocampal slices when chemical synaptic transmission is blocked by low-calcium artificial cerebrospinal fluid solution (Jefferys 1995; Jefferys and Haas 1982; Konnerth et al. 1984; Schweitzer et al. 1992; Taylor and Dudek 1982). This nonsynaptic epileptiform activity can remain stable for many hours, with individual bursts even lasting up to tens of seconds. Therefore the activity is consistent with ictal epileptiform activity. Excessive excitation and hypersynchronization emerging from nonsynaptic mechanisms are thought to be two important keys for the development of the low-Ca2+ induced epileptic activity.
Within the hippocampus it has been reported that the concentration of Ca2+ decreases while the concentration of K+ increases during after-discharges in vivo (Krnjevic et al. 1980; Somjen and Giacchino 1985). In addition, as early as 1974, Kaczmarek and Adey mentioned that regular and spontaneous seizure activity could be induced in cat cortex following superfusion with a low-calcium solution (0.75 mM) for more than 3 h (Kaczmarek and Adey 1974, 1975). These observations were not investigated further, and the effects of low calcium in the hippocampus in vivo have not been studied yet.
Nonsynaptic epilepsy has been studied almost exclusively in vitro with hippocampal slices; however, its clinical relevance has been questioned. In this paper, we test the hypothesis that nonsynaptic activity can be generated in vivo in the hippocampus of rats. We report three different types of epileptiform activity generated by lowering [Ca2+]o using the calcium chelator EGTA.
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METHODS |
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All procedures used in this study were approved by the Institutional Animal Care and Use Committee, Case Western Reserve University, Cleveland. Adult Sprague-Dawley rats (200–400 g) were anesthetized with urethane (1.25–1.5 g/kg, ip) and placed in a stereotaxic apparatus. Body temperature was maintained at 37°C with a heating pad. The skull over the left cortex was opened, and the neocortex overlying the dorsal hippocampus was removed. Artificial cerebrospinal fluid (ACSF) was warmed to approximately 37°C and placed over the surface of the exposed dorsal hippocampus and was replaced every 5 min throughout the experiment.
Solutions and drugs
Normal ACSF consisted of (in mM) 124 NaCl, 5 KCl, 1.25 KH2PO4, 2 CaCl2, 1.5 MgSO4, 26 NaHCO2 and 2 g/l D-glucose. Calcium chelator EGTA-containing ACSF was made by replacing CaCl2 with 5 or 10 mM EGTA. Recovery ACSF was made by increasing the concentration of CaCl2 to 4 mM. In some experiments, the KCl concentration was increased to 10 mM. Excitatory postsynaptic amino acid antagonists 6,7-dinitroquinoxaline-2,3-dione (DNQX) and D-(–)-2-amino-5-phosphonopentanoic acid (D-APV) were used to block the AMPA/KA glutamate receptor and the N-methyl-D-aspartate (NMDA) glutamate receptor, respectively. All chemicals were obtained from Sigma.
Recording of spontaneous and evoked potentials
Eight-channel silicon recording probes (4mm200) were provided by the Center of Neural Communication Technology, University of Michigan. The distance between electrodes in the probe was 200 µm. Only four channels were used to record field potentials in the CA1 pyramidal stratum and in the CA1 stratum radiatum. Stimulus electrodes were made from pairs of insulated Nichrome wires (80 µm diam) with a 0.5-mm vertical tip separation. The recording probe was positioned in the left hippocampal CA1 area (AP–3.0, ML 2.6). Patterns of the evoked potentials guided vertical positioning of the recording probe (Kloosterman et al. 2001). The stimulus electrode was inserted into the left hippocampus (AP–2.0, ML 2.3) for stimulation of Schaffer collaterals. To induce maximal orthodromic-evoked potentials in CA1, a stimulus pulse of 0.1-ms duration and 0.3- to 0.4-mA current was used. In some preparations, a stimulus electrode was also placed on the alveus to induce antidromic-evoked potentials in CA1. A stainless steel screw was fixed in the bone of the nose served as ground electrode. Three other screws were fixed on the skull over frontal cortex, occipital cortex, and cerebellum on the right side of the brain to record spontaneous electrocorticograms (ECoG's).
CA1 field potential signals were amplified 1,000 times by a model 1700 four-channel amplifier (A-M System) with filter frequency ranges of 0.1–500 Hz for spontaneous potentials and 0.1 Hz–10 KHz for evoked potentials. ECoG's were amplified 1,000 times by P511 amplifiers (GRASS) with a filter frequency range of 0.1–300 Hz. CA1 spontaneous potentials and ECoG's were sampled at a rate of 1 KHz, and evoked field potentials were sampled at a rate of 20 KHz, respectively, using a PCI-6071E data acquisition system (National Instruments) before they were stored on hard disk for off-line analysis.
Data are expressed as mean ± SD. A paired Student's t-test (2-tailed) was used for statistical comparisons.
Experiment protocol
Immediately following exposure of the hippocampus, normal ACSF was perfused for 2–3 h to allow recovery from surgery. Stimulation and recording probes were placed, and baseline signals of both spontaneous and evoked potentials were recorded at the end of this period. EGTA-containing ACSF was then applied for 80–120 min. Finally, the perfusion solution was changed to ACSF solution with 4 mM CaCl2 to recover [Ca2+]o in the hippocampus. To investigate the effect of EGTA and KCl, different concentrations of EGTA and KCl were used in three groups: 1) EGTA 5 mM, KCl 5 mM (n = 9); 2) EGTA 10 mM, KCl 5 mM (n = 4); and 3) EGTA 10 mM, KCl 10 mM (n = 3). A fourth group (n = 8) was used to study the effect of excitatory amino acid blockade. In this group, ACSF with DNQX (80 µM) and D-APV (100 µM) and KCl (10 mM) was applied for 40–60 min prior to the addition of 10 mM EGTA.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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The latency between the addition of EGTA and appearance of the wave forms, duration, amplitude, and number of trials where these wave forms appeared are summarized in Table 1.
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Early-bursts
In the three experimental groups without D-APV and DNQX, application of EGTA solution produced early-bursts (n = 14/16) with a latency of 3.6 ± 2.1 min. Figure 2A illustrates a four-channel recording of a typical early-burst. Insets on the left and right are orthodromic-evoked responses recorded before and after the burst, respectively, showing multiple PSs. The shapes of evoked responses indicate that the second electrode was located near the CA1 pyramidal layer and the third and fourth electrodes were located in CA1 s. radiatum. Both the frequency and amplitude of spikes within the burst varied considerably throughout the burst. Figure 2B shows three epochs of the burst at a higher time resolution, demonstrating the large frequency changes within the burst. Waveforms in the s. radiatum (channels 3 and 4) are out of phase from waveforms near the pyramidal layer (channel 2).
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Immediately preceding the early-burst (3.2 ± 2.1 min following the application of EGTA), the PS amplitude (the sum of multiple peaks) of the orthodromic-evoked potential increased significantly (199 ± 72%, P = 0.011, paired t-test vs. baseline), although the excitatory postsynaptic potential (EPSP) decreased (84 ± 15%; P = 0.027, paired t-test vs. baseline; Fig. 3A). This indicated an increase in excitability of CA1 cells.
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Slow-waves
Slow-waves appeared in the CA1 spontaneous field potential about 24 ± 8.5 min following the application of EGTA ACSF. Those waves could remain throughout the whole EGTA perfusion period, although their frequency and amplitude were quite variable. They appeared as regular slow-waves (Figs. 4A and 1C), as slow-waves with late-bursts and/or with superimposed spikes (Figs. 4B and 1D), as spindle groups (Fig. 4C), or as spindle groups with trains of spike analogous to those seen in vitro experiments in low Ca2+ (Fig. 4D). This train of spike was termed in-vitro–like-burst. The lowest frequency of slow-wave was 0.69 ± 0.79 Hz, and its amplitude in the s. radiatum was larger than in the pyramidal layer. However, in-vitro–like-bursts superimposed on the slow-waves had a larger amplitude in the pyramidal layer (Table 1). The duration of in-vitro–like-bursts varied from 0.02 (single spike) to 5.8 s, with a frequency of 30 ± 7.1 Hz. In addition, both slow-wave activity and invitro–like-bursts in the s. radiatum were out of phase from those in the pyramidal layer (Fig. 4).
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Following a series of slow-waves, a spreading depression (SD)-like potential sometimes appeared with a slow propagation speed from the s. radiatum toward the pyramidal layer. It was similar to the SD that has often been observed during electrically or chemically induced after-discharges (Bragin et al. 1997; Herreras et al. 1994).
During periods of maximal slow-wave activity, synaptic transmission was mostly blocked, as indicated by disappearance of the PSs and only 16 ± 14% (or 11 ± 9% in the D-APV and DNQX group) of EPSPs remaining in the orthodromicevoked potential (Fig. 3).
Late-bursts
Late-bursts were observed in the experimental groups with high EGTA (10 mM) and with high EGTA (10 mM) and high KCl (10 mM; Table 1). Generally, they occurred during the slow-wave period at an average frequency of one burst per 6.0 ± 3.7 min. Two typical late-bursts are illustrated in Fig. 5, A and B. The late-burst usually started with spikes at a high frequency of 40 Hz, and then the frequency slowed. This feature is demonstrated clearly in the high-pass filtered signals (>6 Hz) and in the expanded insets. Slow-waves continued before and after the late-bursts. The maximum amplitude of late-bursts was in the s. radiatum (Table 1), and they were in phase with waves in the pyramidal layer (Figs. 4B and 6D).
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Effects of excitatory amino acid antagonists
In eight preparations, D-APV and DNQX solution with KCl 10 mM was perfused for about 1 h before the use of EGTA. The synaptic transmission was mostly blocked by D-APV and DNQX, as indicated by the disappearance of the PSs and only 31 ± 23% of EPSPs remaining in the orthodromic-evoked response (Fig. 3B and Fig. 6B).
Following the onset of EGTA perfusion, no early-burst occurred in the spontaneous potential, indicating that synaptic transmission might play a role in the generation of an early-burst (see DISCUSSION). Slow-waves with or without in-vitro–like-bursts persisted in the presence of D-APV and DNQX (Fig. 6, C and D). There was no significant difference in the frequency or amplitude of slow-waves between preparations with or without the presence of D-APV and DNQX. Late-burst also developed in the preparations with D-APV and DNQX (Fig. 6D). These results suggest that slow-waves and late-bursts are generated by nonsynaptic mechanisms.
Propagation of hippocampal activity into cortical ECoG's
ECoG'ss were always recorded simultaneously with CA1 potentials. Early-bursts in CA1 could propagate into the cortex (n = 7). The largest potential change was always observed in the occipital ECoG (Fig. 7A). In some preparations, large amplitude late-bursts also invaded into the cortex (n = 5; Fig. 7B). However, no obvious change in the electrical activity of the cortex was seen during slow-wave periods.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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A common method to induce low-Ca2+ activity in a hippocampal slice is to perfuse the slice with ACSF containing a concentration of Ca2+ below 0.5 mM and a concentration of K+ over 5 mM (Jefferys 1995; Schweitzer et al. 1992). Zero CaCl2 and even EGTA-containing (1–3 mM) ACSF solutions have also been used to create nanomolar Ca2+ environments (Watson and Andrew 1995; Yaari et al. 1983) or to speed up the appearance of epileptic activity (Konnerth et al. 1986). In vivo, the diffusion of chemicals into the hippocampus is more difficult, especially into deep tissues. Therefore solutions with high concentrations of EGTA (5 or 10 mM) were used to lower the Ca2+ in our experiments. Also, a high concentration of KCl (10 mM) was used in some preparations for the same reason. The complete disappearance of the orthodromic-evoked PSs demonstrated that Ca2+ was lowered and synaptic transmission was blocked efficiently. However, small EPSPs could still appear, especially in deeper s. radiatum where [Ca2+]o might not be low enough for a complete disappearance of EPSPs. Nevertheless, it is clear that the change in extracellular Ca2+ was responsible for inducing all three types of CA1 epileptiform activity, since following the application of a recovery ACSF solution with high CaCl2, spontaneous and evoked activities recovered.
Low-Ca2+ solutions generate epileptic activity by inducing hyperexcitability and enhancing synchronization. The excessive excitability is thought to result from reducing the surface-charge screening and the action potential threshold, as well as by blocking calcium-activated hyperpolarizing currents and reducing synaptic GABAergic inhibition. Other nonsynaptic synchronization mechanisms are responsible for effects including field effects, gap junctions, and fluctuations of elevated extracellular K+ concentration (Bikson et al. 1999, 2002; Dudek et al. 1998; Jefferys 1995; Schweitzer et al. 1992; Watson and Andrew 1995). Presumably, these mechanisms, well studied in vitro, also play an important role in vivo.
Excitatory postsynaptic amino acid antagonists D-APV and DNQX did not eliminate the slow-wave and the late-burst. This further suggests that these activities do not depend on synaptic transmission. A GABA antagonist was not used in our preparation because GABA would inhibit neural activity even if it was released in the low-calcium situation.
Another factor appears to be involved in the origin of the early-burst. During [Ca2+]o washout from a hippocampal slice, it has been shown that inhibitory synaptic transmission in CA1 is impaired earlier than excitatory synaptic transmission (Jones and Heinemann 1987). When the extracellular [Ca2+]o falls to a concentration between 1.03 and 0.7 mM, inhibitory postsynaptic potentials (IPSPs) are abolished; however, EPSPs are abolished only after [Ca2+]o reach between 0.78 and 0.26 mM. In our experiments, at the beginning of [Ca2+]o washout, the multiple PSs in both orthodromic- and antidromic-evoked potentials (Figs. 1B, 2A, and 3A) were quite similar to activity generated in a [Ca2+]o of 0.7–0.5 mM in vitro (Konnerth and Heinemann 1983; Schweitzer et al. 1992). Therefore the imbalance between excitatory and inhibitory synaptic transmission during the early stage of [Ca2+]o washout might also play a role in inducing the ictal-like early-bursts. The synaptic origin of the early-burst is further supported by the observation that the early-burst was eliminated by the application of D-APV and DNQX. Seizure activity reported in cat cortex using a solution with 0.75 mM Ca2+ (Kaczmarek and Adey 1974, 1975) presumably developed by a similar mechanism as the early-burst seen in this work.
Comparison of low-calcium effects in vivo with in vitro
Slow-waves observed in our preparations retain the following characteristics of low-Ca2+ depolarization activity in vitro: 1) the slow appearance of this activity after the use of EGTA is similar to the slow onset of low Ca2+ activity in vitro; 2) excitatory postsynaptic amino acid antagonists D-APV and DNQX cannot prevent the slow-waves as previously reported in low-Ca2+ depolarization shifts in vitro (Bikson et al. 2002; Dudek et al. 1990); 3) the phase of the slow-wave in CA1 s. radiatum is opposite to that in the pyramidal layer, which is consistent with the polarity of large depolarization shifts induced by low-Ca2+ in vitro (Haas and Jefferys 1984; Leschinger et al. 1993; Yaari et al. 1986); 4) PS bursts are superimposed on the depolarization shifts of slow-waves as observed in vitro; and 5) spreading depression sometimes can follow the slow-waves as previously observed in vitro (Yaari et al. 1986).
However, the frequency of slow-waves in vivo (0.69 ± 0.79 Hz) is higher than that of depolarization waves in vitro (0.05–0.33 Hz) (Konnerth et al. 1986). In addition, the amplitude and frequency of slow-waves in vivo vary considerably, while the depolarization waves in vitro are stable throughout low-Ca2+ conditions.
The late-bursts with high-frequency spikes observed in our experiments usually appear long after synaptic transmission is blocked and could not be abolished by D-APV and DNQX. These features are similar to the intensive burst superimposed on depolarization shift in vitro. However, although both the late-bursts and the in-vitro–like-bursts observed here superim-pose on slow-waves and share a similar frequency range, they are different in several aspects. First, the duration of late-bursts (40 ± 23 s) is much longer than maximal duration (5.8 s) of the in-vitro–like-bursts. Second, the maximal amplitude of the late-burst is observed in the s. radiatum, while that of the invitro–like-burst is observed in the pyramidal layer (Table 1). Third, the late-burst in the s. radiatum is in phase with that in the pyramidal layer, while the in-vitro–like-burst is out of phase from that in the pyramidal layer. Finally, the late-burst can appear on both negative and positive phases of slow-waves, while the in-vitro–like-burst always appears on depolarization shifts of slow-waves. Therefore the late-burst and the in-vitro–like-burst are two different types of activity.
Comparison of the low-calcium activity in vivo with human epileptic activity in hippocampus
One of the interesting results of these experiments is the similarity of the nonsynaptic activity seen in this study to two types of epileptic activity that occur in the hippocampus of patients with temporal lobe epilepsy (Engel 1989, 1990, 1996; Spencer and Spencer 1994; Wennberg et al. 2002). One type of activity often appears as regularly or irregularly repetitive high-amplitude sharp activity (<13 Hz) (Wennberg et al. 2002) or spike-and-wave discharges (3 Hz) (Engel 1989). This activity is similar to the slow-waves or slow-waves with superimposed spikes observed in the experiments reported above. The frequency of the sharp activity in a human hippocampus can be as low as 1 Hz (see Figs. 4–18 in Engel 1989). The other type of activity is called poly-spike activity, with a frequency of >13 Hz (Wennberg et al. 2002) or low-voltage fast activity (Engel 1989). It is similar to the late-burst in our observations. Both of these types of seizure activity in a human hippocampus can evolve into one another, which is similar to the slow-waves and late-bursts seen in this in vivo hippocampal preparation. Therefore these low-calcium epileptiform activity in an intact hippocampus could be a useful model of human epilepsy.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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DISCLOSURES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONCONCLUSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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Address for reprint requests and other correspondence: D. M. Durand, Dept. of Biomedical Engineering, 112 Wickenden Bldg., Case Western Reserve Univ., 10900 Euclid Ave., Cleveland, OH 44106 (E-mail: dxd6{at}po.cwru.edu).
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REFERENCES |
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