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Volume 17, Number 23, Issue of December 1, 1997
CA3-Driven Hippocampal-Entorhinal Loop Controls Rather than Sustains In Vitro Limbic Seizures
Michaela Barbarosie and Massimo Avoli Research Group on Cell Biology of Excitable Tissues, Montreal Neurological Institute, Departments of Neurology and Neurosurgery, and of Physiology, McGill University, Montreal, Québec, Canada H3A 2B4
ABSTRACT
Continuous application of 4-aminopyridine (4-AP, 50 µM) to combined slices of hippocampus-entorhinal cortex obtained from adult mice induces (1) interictal discharges that initiate in the CA3 area and propagate via the hippocampal regions CA1 and subiculum to the entorhinal cortex and return to the hippocampus through the dentate gyrus; and (2) ictal discharges that originate in the entorhinal cortex and propagate via the dentate gyrus to the hippocampus proper. Ictal discharges disappear over time, whereas synchronous interictal discharges continue to occur throughout the experiment. Lesioning the Schaffer collaterals abolishes interictal discharges in CA1, entorhinal cortex, and dentate gyrus and discloses entorhinal ictal discharges that propagate, via the dentate gyrus, to the CA3 subfield. Interictal discharges originating in CA3 also prevent the occurrence of ictal events generated in the entorhinal cortex during application of Mg2+-free medium. In both models, ictal discharge generation recorded in the entorhinal cortex after Schaffer collateral cut is prevented by mimicking CA3 neuronal activity through rhythmic electrical stimulation (0.25-1.5 Hz) of the CA1 hippocampal output region. Our findings demonstrate that interictal discharges of hippocampal origin control the expression of ictal epileptiform activity in the entorhinal cortex. Sectioning the Schaffer collaterals may model the chronic epileptic condition in which cell damage in the CA3 subfield results in loss of CA3 control over the entorhinal cortex. Hence, we propose that the functional integrity of hippocampal output neurons may represent a critical control point in temporal lobe epileptogenesis.
Key words: hippocampus; entorhinal cortex; seizures; CA3; 4-aminopyridine; Mg2+-free
INTRODUCTION
It is believed that seizures originating in the entorhinal cortex propagate to the hippocampus proper and reenter the entorhinal cortex in a loop that functions in a "loop-gain" manner to sustain and reinforce long-lasting epileptiform activity (Paré et al., 1992
; Jones, 1993
We and others have demonstrated in rat combined hippocampus-entorhinal cortex slices that prolonged epileptiform discharges initiate in the entorhinal cortex and propagate to the hippocampal formation (Jones and Lambert, 1990
In the present study, we have used combined hippocampal-entorhinal cortex slices obtained from adult mouse to investigate the role of the hippocampal-entorhinal loop in two different in vitro models of epileptiform discharge. Owing to the reduced size of the animal brain, we assumed that reciprocal connectivity between the entorhinal cortex and the hippocampus may be preserved. Our findings indicate that this was indeed the case. In particular, we addressed the following questions: (1) Does the hippocampal-entorhinal loop subserve a sustaining purpose? (2) What is the interaction between ictal and interictal epileptiform activity in the initiation, propagation, and control of seizures that may lead to an epileptic condition? Herein, we introduce a novel, surprising role that the hippocampal-entorhinal loop may play in limbic seizures and thus in temporal lobe epilepsy. We demonstrate that when interictal epileptiform activity of CA3 origin is allowed to propagate within this loop, rather than contributing to intensify seizure activity, reentry serves to control and thus to prevent seizure generation. On the contrary, when the loop is discontinued, seizure activity is allowed to be generated in the entorhinal cortex and to propagate to the hippocampus proper via the dentate gyrus.
MATERIALS AND METHODS
Adult, male, CD-1 or BALB/c mice (25-35 gm) were decapitated under halothane anesthesia. Their brains were quickly removed and were placed in cold (1-4°C), oxygenated artificial CSF (ACSF). Horizontal slices (550 µm thick) were cut with a vibratome and then transferred to a tissue chamber where they lay between oxygenated ACSF and humidified gas (95%O2, 5%CO2) at 32-33°C. ACSF composition was (in mM): NaCl 124, KCl 2, KH2PO4 1.25, MgSO4 2, CaCl2 2, NaHCO3 26, and glucose 10. 4-AP (50 µM) was bath-applied. In some experiments, epileptiform discharges were induced by Mg2+-free ACSF. Chemicals were acquired from Sigma (St. Louis, MO).
Slices included the entorhinal cortex and the hippocampus proper that also comprised the subiculum and the dentate gyrus. Field potential recordings were performed with ACSF-filled microelectrodes (tip diameter, 8 µm; resistance, 2-10 M
) that were positioned in the medial portion of the entorhinal cortex, the granule cell layer of the dentate gyrus, and the CA3 or CA1 stratum radiatum. Signals were fed to high-impedance amplifiers, displayed on a Gould-pen chart recorder, and also digitized and stored on videotape for subsequent analysis.
A series of cutting experiments was performed using a microknife to establish the origin and the pathway used by the epileptiform activity to propagate in the slice. Time delay measurements for initiation of epileptiform discharges were performed by taking as a temporal reference the first deflection from the baseline recording. Extracellular stimulation was performed with a bipolar stainless steel electrode that was placed in the stratum radiatum of the CA1 subfield or in the deep layers of the entorhinal cortex. Stimulation parameters were intensity, 0.1-0.5mA; duration, 100 µsec; and frequency, 0.5-1.5 Hz. The stimulation intensity was adjusted to obtain an interictal discharge. Measurements in the text are expressed as mean ± SD, and n represents the number of slices studied. Data were compared with the Student's t test or the ANOVA test and were considered significantly different if p < 0.05.
RESULTS
Properties of 4-AP-induced epileptiform discharges
Simultaneous field potential recordings in CA3, dentate gyrus, and entorhinal cortex were performed in >70 combined hippocampus-entorhinal cortex slices. Most recordings in the entorhinal cortex were done in the deep layers (~500-800 µm from the pia), where maximal field potential amplitudes were detected (cf. Avoli et al., 1992
Fig. 1. Spontaneous epileptiform activity recorded at 1 and 2 hr during continuous bath application of 4-AP. Simultaneous field potential recordings were made in the CA3 stratum radiatum, the deep layers of the entorhinal cortex, and the dentate granule cell layer. Ictal discharge, recorded at 1 hr, is indicated by continuous line, interictal discharges by arrows, and robust interictal discharges with afterdischarge component by arrowheads. At 2 hr during 4-AP application, ictal discharges disappear. In this and the following figures, EC and DG stand for entorhinal cortex and dentate gyrus, respectively.
[View Larger Version of this Image (63K GIF file)]
The ictal epileptiform activity induced by 4-AP changed over time. As illustrated in Figure 1 (2 hr), ictal discharges disappeared and were replaced by continuous interictal events, which remained synchronous in the entorhinal and hippocampal regions. In nine slices, the activity was monitored from the start of 4-AP application throughout a period of 4 hr. The percentage of slices generating ictal discharges at different times after the onset of 4-AP application is shown in Figure 2A. 
Fig. 2. A, Percentage histogram of slices generating ictal discharges at different times of 4-AP application. These slices (n = 9) were recorded for >4 hr. B, Expanded traces of interictal (a) and ictal discharges (b) induced by 4-AP (~1 hr) in an intact entorhinal-hippocampal combined slice. In a, the interictal discharge initiates in the CA3 region and propagates to the entorhinal cortex and the dentate gyrus; arrows point at the late components of the interictal discharge recorded in CA3. In b, the ictal discharge is preceded by an interictal event with temporal profile similar to that seen in a, whereas the site of origin of the ictal discharge appears to occur in the entorhinal cortex. Dotted lines in a and b were positioned at the time of the earliest visible deflection in the three field potential recordings.
[View Larger Version of this Image (17K GIF file)]
By contrast, interictal discharges did not show over time any detectable change at the field potential level. In six slices we investigated the site of origin and the modalities of propagation of the interictal discharges in the hippocampal-entorhinal network by performing time delay measurements. This type of analysis showed that interictal events initiated in CA3, propagated (presumably via the CA1 and the subiculum) to the entorhinal cortex, and returned to the hippocampus through the dentate gyrus to give rise to a second or third interictal component in CA3 both when ictal discharges were still present (Fig. 2B, arrows) and when ictal activity had disappeared (see Fig. 4B, before SC cut). The time delays between the interictal discharges in the different areas are illustrated in Table 1. 
Fig. 4. Effects induced by sectioning the Schaffer collaterals and the perforant pathway on epileptiform discharges recorded ~2 hr after continuous application of 4-AP. A, Interictal discharges are recorded in CA3, entorhinal cortex, and dentate gyrus in the intact slice (traces, left). Sectioning the Schaffer collaterals abolishes the interictal discharges in entorhinal cortex and dentate gyrus and discloses an ictal discharge that is simultaneously recorded in CA3, entorhinal cortex, and dentate gyrus (traces, middle). Further cutting of the perforant path abolishes the propagation of the ictal discharge to the entorhinal cortex and dentate gyrus (traces, right). B, Expanded traces from the experiment shown in A demonstrate that interictal discharges reenter CA3. They comprise two components in the CA3 of the intact slice (Before SC cut), whereas after sectioning the Schaffer collaterals, a single component is left (After SC cut, Interictal). The onset of an ictal discharge recorded after Schaffer collateral cut is also shown (After SC cut, Ictal). C, Quantitative summary of the effects induced by Schaffer collateral cut on the number of interictal discharge components in CA3, entorhinal cortex (EC) and dentate gyrus (DG) (n = 6; p < 0.05).
[View Larger Version of this Image (31K GIF file)]
Table 1. Time delays for interictal discharges
CA3 EC (msec)
EC DG 28.0 ± 12.1 22.5 ± 12.8 35.0 ± 23.8 n = 6 n = 6 n = 6 Changes induced by neuronal pathway sections
It was difficult from time delay measurements to determine the site of origin of the ictal discharges. Therefore, we established the origin and pattern of propagation of the synchronous activities induced by 4-AP by cutting selective neuronal pathways. Severing the perforant path abolished the occurrence of ictal discharges in the hippocampus proper without affecting the interictal activity of CA3 origin or modifying the ictal discharges in the entorhinal cortex (n = 3; Fig. 3A).
Fig. 3. Spontaneous epileptiform activity recorded during application of 4-AP (~1 hr) in a combined hippocampal-entorhinal cortex slice before and after selective neuronal pathway sectioning. A, Changes in 4-AP-induced activity before and after cut of the perforant path indicate that the ictal discharges originate in the entorhinal cortex. B, Effects induced by Schaffer collateral cut further demonstrate that interictal discharges initiate in the CA3 subfield, because they are abolished in the entorhinal cortex and dentate gyrus. Note also that after Schaffer collateral cut, the ictal discharge duration is increased (n = 6; p < 0.05).
[View Larger Version of this Image (36K GIF file)]
To further establish the functional role of interictal discharge reentry to CA3 subfield (as indicated by the delay measurements) and its effect on entorhinal epileptiform activity, we sectioned the Schaffer collaterals. We reasoned that a cut of the Schaffer collaterals would selectively prevent propagation of CA3 hippocampal activity to the hippocampal efferent regions CA1 and subiculum, thus preventing hippocampal activity from reaching the entorhinal cortex. In slices that displayed ictal discharges, this section resulted in (1) blockade of interictal discharges in all but the CA3 subfield and (2) increase in the duration of ictal events from 36 ± 20.1 sec under control conditions to 69 ± 35.1 sec after Schaffer collateral cut (n = 6; Fig. 3B).
Moreover, in slices in which ictal discharges had stopped to occur over time, the Schaffer collateral section made (1) interictal events disappear in nonCA3 subfields and (2) ictal events reappear. These ictal discharges lasted 30-160 sec, occurred at intervals of 1.3-12.5 min, and were synchronous in entorhinal cortex, dentate, and CA3 areas (n = 34; Fig. 4A). In our preparation, interictal discharges recorded in CA3 consisted of multiple components (number of components in intact slice = 2.7 ± 0.7; n = 6) when the hippocampal-entorhinal circuit was intact (Fig. 4B,C). After sectioning the Schaffer collaterals, interictal discharges in entorhinal cortex and dentate gyrus ceased to occur although the number of interictal discharge components in CA3 was reduced to 1.1 ± 0.4 (n = 6; Fig. 4B,C). In very few slices, interictal discharges of entorhinal cortex origin reminiscent of those induced by pilocarpine (Nagao et al., 1996 
Fig. 7. A, Continuous recordings showing the effect of CA1 stimulation at 1 Hz on the 4-AP-induced epileptiform activity recorded after Schaffer collateral cut. Note the persistence of interictal discharges, presumably of entorhinal origin, before and after the ictal activity. Ictal discharge does not occur during the stimulation period and re-appear on termination of the stimulation. B, Time histogram showing the effect of low-frequency stimulation on ictal discharge occurrence (p < 0.05 for both stimulation protocols). Data were obtained from eight slices for the first stimulation and four slices for the second stimulation protocol.
[View Larger Version of this Image (79K GIF file)]
Hippocampal control of low-Mg2+-induced epileptiform discharges
To ensure that the results obtained with 4-AP could also be reproduced with another in vitro type of epileptiform discharge, we repeated these experiments during application of Mg2+-free ACSF (n = 5). This procedure is known to induce synchronized interictal discharges in the isolated hippocampal slice (Tancredi et al., 1990
Spontaneous, synchronous events matured over time (~2 hr) to become robust, interictal discharges that lasted 1.3 ± 0.8 sec, occurred at 0.3 ± 0.1 Hz (n = 5), and appeared in all areas of the combined slice (Fig. 5, top). These interictal discharges initiated in the hippocampus proper (most often CA3), propagated to the entorhinal cortex, and returned to the hippocampus via the dentate gyrus (Fig. 5, inset, top). In the unlesioned slice, interictal discharges in CA3, entorhinal cortex, and dentate gyrus consisted of multiple components (Fig. 5, inset, bottom). Cutting the Schaffer collaterals reduced the number of interictal discharge components in CA3 and dentate gyrus to one and abolished interictal activity in the entorhinal cortex (Fig. 5, bottom). In addition, this procedure disclosed ictal discharges that occurred in apparent synchronous manner in all areas (Fig. 5, bottom); they lasted 19.6 ± 9.5 sec and repeated at an interval of 49.1 ± 25.4 sec (n = 5). Sectioning the perforant path (n = 2) abolished seizure propagation to the dentate gyrus and CA3 subfield, further demonstrating that ictal discharges originate in the entorhinal cortex (not illustrated). 
Fig. 5. Spontaneous epileptiform activity induced by Mg+2-free ACSF before and after Schaffer collateral cut. Before the lesion (top), synchronized interictal discharges are recorded in CA3, entorhinal cortex, and dentate gyrus. Sectioning the Schaffer collaterals (bottom) abolishes interictal discharges in the entorhinal cortex and discloses ictal epileptiform activity that is recorded in the three areas. Expanded traces of the experiment shown in the top and bottom are illustrated in the middle. Note that before the Schaffer collateral cut Mg+2-free-induced interictal discharges consist of multiple components, whereas after the cut (Interictal) they are markedly reduced in duration and number of events. Note also that the ictal discharge (Ictal) is initiated in the entorhinal cortex.
[View Larger Version of this Image (29K GIF file)]
Blockade of ictal discharges by low frequency stimulation
To further demonstrate that the interictal events originating in CA3 function in a network to prevent ictal activity from being generated in the entorhinal cortex, we stimulated the stratum radiatum of the hippocampal output region CA1 (Amaral and Witter, 1989
Fig. 6. Effect induced by extracellular stimuli delivered in the CA1 subfield (1 Hz) on the Mg+2-free-induced ictal activity recorded after Schaffer collateral cut. A-C, Continuous recordings demonstrate that low-frequency stimulation prevents the occurrence of ictal discharges that reappear on termination of the stimulation.
[View Larger Version of this Image (40K GIF file)]
DISCUSSION
In this study we used combined mouse hippocampal-entorhinal slices in which reciprocal connections between hippocampus and entorhinal cortex are preserved to investigate the interaction of these structures in two in vitro models of limbic seizures. Clinical neurophysiological investigations have shown that functional connections between hippocampus and entorhinal cortex exist in patients with temporal lobe epilepsy (Ruteki et al., 1989Reentry within the entorhinal-hippocampal loop
In the intact, normal brain, sharp waves originating in the hippocampus (most probably in CA3) propagate to the deep layers of the entorhinal cortex and then to other brain regions but not to the superficial layers of the entorhinal cortex, and thus they do not reenter the hippocampus (Chrobak and Buzsáki, 1994
In the present study, spontaneous potentials induced by either 4-AP or Mg+2-free medium were recorded synchronously in all areas of the combined slice, suggesting that reciprocal connections between the entorhinal cortex and the hippocampus proper do exist in our preparation and, thus, that epileptiform discharges do propagate within the hippocampal-entorhinal loop. Lesioning the Schaffer collaterals influenced the epileptiform activity recorded in the entorhinal cortex in two ways. First, it blocked the occurrence of interictal discharges originating in the hippocampus proper. In particular, we showed that the CA3 interictal discharges recorded in the intact slice consist of multiple components in both the 4AP and Mg2+-free models. Schaffer collateral cut during 4-AP application abolished interictal discharge components in the entorhinal cortex and the dentate gyrus and reduced them to unity in CA3. This procedure also blocked the occurrence of Mg2+-free-induced interictal discharge components in the entorhinal cortex and reduced the number to unity in both CA3 and dentate areas. Second, Schaffer collateral lesion disclosed the appearance of robust ictal discharges in both 4AP and Mg+2-free conditions. Ictal discharges induced by 4AP or Mg+2-free ACSF in rat combined slices originate in the entorhinal cortex (Jones and Heinemann, 1988
Taken together, these data demonstrate that interictal activity requires an intact hippocampal-entorhinal loop to propagate to all areas of the combined slice and to reenter the hippocampus after having propagated to the entorhinal cortex. Moreover, these findings reveal that if ictal activity does reenter the hippocampal-entorhinal loop, the result is likely to have no reinforcing effect. In fact, ictal discharges, in contrast to interictal activity, are favored by a discontinued loop, in which hippocampal output activity does not reach the entorhinal cortex. Thus our work demonstrates that contrary to the common view, amplification of epileptiform activity through the hippocampal-entorhinal loop occurs in the hippocampus (most probably in CA3) for the interictal, not in the entorhinal cortex for the ictal discharge, and that the role of reentrant activity is to prevent rather than to sustain prolonged ictal events. Interictal-ictal interaction
The presence of a preserved hippocampal-entorhinal synaptic loop through which epileptiform activity can propagate has allowed us to determine the interaction between ictal and interictal discharges, each of which is generated at distinct sites within the circuit. Some reports have proposed that interictal activity contributes to the transition from interictal to ictal discharge (Prince et al., 1983Acute models with chronic properties
Human temporal lobe epilepsy is associated with hippocampal sclerosis in which dentate hilus, CA3, and CA1 neurons are lost (Gloor, 1991; Wieser et al., 1993
The acute in vitro mouse model described here may address directly the question of whether cell loss alone can be a cause of chronic epilepsy. Sectioning the Schaffer collaterals in our slice preparation may selectively mimic the cell damage and synapse loss observed in animal models of temporal lobe epilepsy (without any other plastic changes). Therefore, our findings reveal that functional CA3 neurons and hippocampal outputs are critical in controlling the chronic state of spontaneous recurrent seizures. Nagao et al. (1994)
Ictal activity in the entorhinal cortex is elaborated and sustained by an intrinsic excitatory circuit within this structure (Ijima et al., 1996
FOOTNOTES
Received July 7, 1997; revised Sept. 9, 1997; accepted Sept. 15, 1997.
This work was supported by Medical Research Council of Canada Grant MT-8109, the Savoy Foundation, Hospital for Sick Children Foundation Grant XG-93056, and the Quebec Heart and Stroke Foundation. M.B. is the recipient of an FRSQ studentship. We thank Siobhán McCann for secretarial assistance.
Correspondence should be addressed to Dr. Massimo Avoli, Montreal Neurological Institute, Room 794, 3801, University Street, Montreal, Québec, Canada H3A 2B4.
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Rat subicular networks gate hippocampal output activity in an in vitro model of limbic seizures
J. Physiol., August 1, 2005; 566(3): 885 - 900.
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Z. Feng and D. M. Durand
Decrease in Synaptic Transmission Can Reverse the Propagation Direction of Epileptiform Activity in Hippocampus In Vivo
J Neurophysiol, March 1, 2005; 93(3): 1158 - 1164.
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T. I. Netoff, R. Clewley, S. Arno, T. Keck, and J. A. White
Epilepsy in Small-World Networks
J. Neurosci., September 15, 2004; 24(37): 8075 - 8083.
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M. D'Antuono, J. Louvel, R. Kohling, D. Mattia, A. Bernasconi, A. Olivier, B. Turak, A. Devaux, R. Pumain, and M. Avoli
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Brain, July 1, 2004; 127(7): 1626 - 1640.
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V. I. Dzhala and K. J. Staley
Transition from Interictal to Ictal Activity in Limbic Networks In Vitro
J. Neurosci., August 27, 2003; 23(21): 7873 - 7880.
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R. Stoop, F. Conquet, B. Zuber, L. L. Voronin, and E. Pralong
Activation of Metabotropic Glutamate 5 and NMDA Receptors Underlies the Induction of Persistent Bursting and Associated Long-Lasting Changes in CA3 Recurrent Connections
J. Neurosci., July 2, 2003; 23(13): 5634 - 5644.
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A. Agmon and J. E. Wells
The Role of the Hyperpolarization-Activated Cationic Current Ih in the Timing of Interictal Bursts in the Neonatal Hippocampus
J. Neurosci., May 1, 2003; 23(9): 3658 - 3668.
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A. Rosati, Y. Aghakhani, A. Bernasconi, A. Olivier, F. Andermann, J. Gotman, and F. Dubeau
Intractable temporal lobe epilepsy with rare spikes is less severe than with frequent spikes
Neurology, April 22, 2003; 60(8): 1290 - 1295.
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H. Khosravani, P. L. Carlen, and J. L. P. Velazquez
The Control of Seizure-Like Activity in the Rat Hippocampal Slice
Biophys. J., January 1, 2003; 84(1): 687 - 695.
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W. H. Theodore, K. Hunter, R. Chen, F. Vega-Bermudez, B. Boroojerdi, P. Reeves-Tyer, K. Werhahn, K. R. Kelley, and L. Cohen
Transcranial magnetic stimulation for the treatment of seizures: A controlled study
Neurology, August 27, 2002; 59(4): 560 - 562.
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T. I. Netoff and S. J. Schiff
Decreased Neuronal Synchronization during Experimental Seizures
J. Neurosci., August 15, 2002; 22(16): 7297 - 7307.
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M. Bikson, S. C. Baraban, and D. M. Durand
Conditions Sufficient for Nonsynaptic Epileptogenesis in the CA1 Region of Hippocampal Slices
J Neurophysiol, January 1, 2002; 87(1): 62 - 71.
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M. D'Antuono, R. Benini, G. Biagini, G. D'Arcangelo, M. Barbarosie, V. Tancredi, and M. Avoli
Limbic Network Interactions Leading to Hyperexcitability in a Model of Temporal Lobe Epilepsy
J Neurophysiol, January 1, 2002; 87(1): 634 - 639.
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G. Sansig, T. J. Bushell, V. R. J. Clarke, A. Rozov, N. Burnashev, C. Portet, F. Gasparini, M. Schmutz, K. Klebs, R. Shigemoto, et al.
Increased Seizure Susceptibility in Mice Lacking Metabotropic Glutamate Receptor 7
J. Neurosci., November 15, 2001; 21(22): 8734 - 8745.
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B. J. Gluckman, H. Nguyen, S. L. Weinstein, and S. J. Schiff
Adaptive Electric Field Control of Epileptic Seizures
J. Neurosci., January 15, 2001; 21(2): 590 - 600.
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M. E. Calcagnotto, M. Barbarosie, and M. Avoli
Hippocampus-Entorhinal Cortex Loop and Seizure Generation in the Young Rodent Limbic System
J Neurophysiol, May 1, 2000; 83(5): 3183 - 3187.
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M. Barbarosie, J. Louvel, I. Kurcewicz, and M. Avoli
CA3-Released Entorhinal Seizures Disclose Dentate Gyrus Epileptogenicity and Unmask a Temporoammonic Pathway
J Neurophysiol, March 1, 2000; 83(3): 1115 - 1124.
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L. L. Thio, M. Wong, and K. A. Y
ABSTRACT
