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1 Montreal Neurological Institute and Departments of Neurology & Neurosurgery, and of Physiology, McGill University, Montreal, QC, H3A 2B4, Canada
2 Dipartimento di Fisiologia Umana e Farmacologia, Università di Roma ‘La Sapienza’, 00185 Rome, Italy
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Abstract |
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(Received 15 April 2005;
accepted after revision 31 May 2005;
first published online 2 June 2005)
Corresponding author M. Avoli: 3801 University, room 794, Montreal, QC, Canada H3A 2B4. Email: massimo.avoli{at}mcgill.ca
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Introduction |
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The subiculum holds a strategic position within the limbic system. Not only does it serve as the major output structure of the hippocampus, getting extensive projections from the CA1 hippocampal region (Finch & Babb, 1981; Witter et al. 1989), but it also projects to various limbic and extralimbic areas including EC layers IV and V (Swanson & Cowan, 1977; Witter et al. 1989), perirhinal cortex (Swanson et al. 1978; Deacon et al. 1983), amygdala (Canteras & Swanson, 1992) and thalamus (Witter et al. 1990; Canteras & Swanson, 1992) (see for review O'Mara et al. 2001). In this study, we sought to identify the role played by the subiculum in intralimbic synchronization using the 4-aminopyridine (4AP) in vitro model of limbic seizures. Here, we report that GABAA receptor-mediated mechanisms confer on the subiculum the ability to gate hippocampal output activity, and thus to dictate the interactions between hippocampal and parahippocampal neuronal networks.
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Methods |
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) that were connected to high-impedance amplifiers. The location of the recording electrodes in the combined hippocampus–EC slice is shown in Fig. 2A. Field responses were induced by applying single shock electrical stimuli (50–100 µs; < 200 µA) delivered through a bipolar, stainless steel electrode (Fig. 3A). Sharp-electrode intracellular recordings were performed in the subiculum with pipettes that were filled with 3 M potassium acetate (tip resistance = 70–120 M). Intracellular signals were fed to a high-impedance amplifier with internal bridge circuit for intracellular current injection. The resistance compensation was monitored throughout the experiment and adjusted as required. The passive membrane properties of the subicular cells included in this study were measured as follows: (i) resting membrane potential (RMP) after cell withdrawal; (ii) apparent input resistance (Ri) from the maximum voltage change in response to a hyperpolarizing current pulse (100–200 ms, < –0.5 nA); (iii) action potential amplitude (APA) from the baseline; and (iv) action potential duration (APD) at half-amplitude. Intrinsic firing patterns of subicular cells were determined from responses to depolarizing current pulses of 500–1000 ms duration. Three neuronal types could be distinguished in this study: strong bursters, weak bursters and regular firing (Staff et al. 2000). Since no differences were observed between these classes in terms of their 4AP-induced activity, strong and weak intrinsic bursters were put together in the ‘bursting’ group (Fig. 5Ab) whilst regular firing cells were placed in the ‘non-bursting’ category (Fig. 6Ab). No fast spiking cells were ever recorded in this study.
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Results |
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As illustrated in Fig. 1A (Control (4AP)) and Fig. 2A, the hippocampus–EC slices (n = 110) included in this study responded to 4AP application by generating three types of synchronous activities (cf. Avoli et al. 1996; Benini et al. 2003): (i) fast interictal discharges (interval of occurrence = 1.6 ± 0.7 s; duration 139 ± 65 ms; n = 25) that were restricted to the hippocampus proper (Fig. 1A, arrows); (ii) slow interictal events that were recorded in both hippocampal and EC regions and could initiate anywhere in the slice (interval of occurrence = 28 ± 15 s; n = 25; Fig. 1A, asterisk); and (iii) long-lasting ictal discharges (interval of occurrence = 236 ± 117 s; duration 64 ± 56 s; n = 25) that originated in EC and could propagate to the hippocampus via the perforant pathway (Fig. 1A, bar). We termed these slices functionally disconnected due to the lack of epileptiform activity propagation from the hippocampus to the EC.
Involvement of GABAA receptors in the epileptiform activity induced by 4AP
Next, we superfused these slices with the GABAA receptor antagonist picrotoxin (50 µM) to establish the role of GABAA receptor-mediated mechanisms in 4AP-induced epileptiform discharges. As shown in Fig. 1, picrotoxin application to these functionally disconnected slices (n = 45) resulted in a dramatic change in the 4AP-induced electrographic activity (Figs 1 and 2). Exposure to this non-competitive GABAA receptor antagonist triggered an initial ictal burst in the EC (Fig. 2B, + Picrotoxin) after which the activity was replaced by robust interictal discharges that initiated in CA3 and propagated sequentially to CA1 and EC (expanded trace in the inset of Fig. 1B, + Picrotoxin). This phenomenon was reproduced with the competitive GABAA receptor antagonist BMI (10 µM, n = 4), thus suggesting that the effect observed was indeed due to hindrance of GABAA receptor function. Transformation of a functionally disconnected slice into one in which hippocampus-driven epileptiform activity could propagate to the EC was fully reversible upon washing out picrotoxin (n = 6) for approx. 2 h (not shown).
GABAA receptor antagonism potentiates interictal activity in the subiculum of functionally disconnected slices
To gain a better understanding of how GABAA receptor antagonism in functionally disconnected slices leads to synchronicity between hippocampus and EC, we analysed the 4AP-induced activity in neuronal networks along the CA3–CA1–subiculum axis (n = 14). This was achieved by obtaining simultaneous field potential recordings from CA3 and EC with two fixed electrodes while a third electrode was moved sequentially from the CA1–CA2 area towards the subiculum at the level of the stratum pyramidale. We found in six of these experiments that the CA3-driven interictal events had similar amplitudes up to the CA1–subiculum border (Fig. 2Ab, Control, +4AP) and then decreased as the recording electrode was placed in subiculum (Fig. 2Ac, Control, +4AP). Moreover, in the remaining experiments (n = 8) interictal events were not recorded during 4AP application in the subiculum concomitant with those seen in the CA3 and CA1 areas (Fig. 4A).
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Stimulation of hippocampal networks elicits response in EC only under GABAA receptor antagonism
To explore further the propagation of hippocampus-driven activity to the EC, we investigated the responses induced in the slice by focal electrical stimuli delivered in CA1, subiculum and EC: (i) in the absence of convulsants (i.e. normal ACSF); (ii) in the presence of 4AP; and (iii) during application of 4AP + PTX (Fig. 3A, B and C, respectively). In these experiments, three recording electrodes were placed in CA1 stratum pyramidale, subiculum and EC deep layers while a stimulating electrode was used to sequentially activate each of these structures.
As expected, a local field response could be recorded in any of the stimulated structures during application of normal ACSF (Fig. 3Aa–c, arrows); in addition, EC stimulation could also elicit some responses in subiculum and CA1. Following 4AP application (Fig. 3B), the local responses increased in amplitude and duration while distant activation could be clearly identified when stimuli were delivered in subiculum and EC (Fig. 3Bb and c, respectively); in contrast, as seen in normal medium, CA1 single shock stimuli (Fig. 3Ba) failed in eliciting subicular (n = 12) or EC responses (n = 24). Finally, during concomitant application of 4AP and picrotoxin, electrical stimuli delivered in any area of the slice induced robust epileptiform discharges in all limbic structures (Fig. 3Ca–c (4AP + PTX)). It should be emphasized that CA1 single-shock stimuli delivered during GABAA-receptor antagonism (Fig. 3Ca) elicited an epileptiform response not only in subiculum, but also in EC (n = 6). Therefore, these observations suggest that GABAA receptor-mediated mechanisms prevent the propagation of both stimulation- and 4AP-induced hippocampal activity to the EC, thereby confirming that the functional disconnectivity between the hippocampus proper and EC was not merely an artifact of the 4AP model itself. In addition, both the potentiation of subicular responses by picrotoxin and the subsequent ability of hippocampus-driven discharges to propagate to the EC suggest that these inhibitory restrictions are most likely at play in the subiculum itself.
Picrotoxin-induced changes in connectivity do not require NMDA receptor function
We also assessed whether NMDA receptors contributed to the changes in connectivity seen during picrotoxin application. To this end we applied high concentrations of the NMDA-receptor antagonist CPP to functionally disconnected slices. As shown in Fig. 4B (+ 30 µM CPP, n = 5) CPP abolished the 4AP-induced ictal events that initiated in EC (Avoli et al. 1996; de Guzman et al. 2004). However, further addition of picrotoxin could still cause an initial ictal event followed by interictal activity in all areas of the slice (Fig. 4C, + 30 µM CPP + 50 µM Picrotoxin). Furthermore, NMDA receptor blockade did not avert the picrotoxin-induced potentiation of the interictal activity or its appearance in the subiculum. (Fig. 4C; n = 5).
Simultaneous field potential and intracellular recordings in the subiculum
The results obtained from the functionally disconnected slices during application of medium containing only 4AP suggest that the subiculum plays a role in gating hippocampal output activity. Furthermore, the ability of CA3-driven epileptiform discharges to propagate to the EC during picrotoxin suggests GABAergic mechanisms in the subiculum might be involved in such a control. Hence, we recorded intracellularly subicular cells along with field potential activity in CA3 and EC in the presence of 4AP and following further addition of picrotoxin.
Two main modes of subicular activity were recorded from these slices during 4AP application. The first type was seen in 20 subicular cells and consisted of bursts of action potentials that followed the interictal discharges recorded in CA3 with time lags of 21 ± 9 ms (n
= 7) (Fig. 5). Electrophysiological characterization of these neurones revealed that 9 out of 20 cells were intrinsic non-bursters (RMP =
–62.9 ± 7.2 mV, Ri
= 66.4 ± 16.3 M, APA = 93.5 ± 13.3 mV, APD = 1.0 ± 0.2 ms; not shown) while the remaining 11 cells (RMP =
–63.4 ± 7.0 mV, Ri
= 60.9 ± 15.6 M, APA = 94.5 ± 6.8 mV, APD = 1.0 ± 0.1 ms) discharged action potential bursts at the onset of an intracellular depolarizing pulse (Fig. 5Ab). Application of picrotoxin to these slices resulted in synchronous interictal discharges occurring in all areas. Furthermore, expanded traces demonstrated that these intracellular events followed CA3 field activity and preceded that of the EC (Fig. 5B, Picrotoxin (late), inset). Intracellular injection of depolarizing pulses indicated that picrotoxin did not modify the intrinsic firing patterns of these cells (not shown).
In contrast, the second group of subicular cells (n
= 11) generated little or no spontaneous action potential firing, while producing robust postsynaptic potentials (PSPs) in association with the CA3-recorded interictal discharges (Fig. 6Aa, Control (4AP)). These PSPs were usually predominated by a hyperpolarizing component (Fig. 6A, Control (4AP), arrows in the lower inset) with a reversal value of approx. –71 mV (not illustrated) suggesting that they were GABAA receptor mediated. In addition, these neurones also generated large isolated hyperpolarizing potentials (Fig. 6A, Control (4AP), asterisk in the lower inset) with a similar reversal potential. Examination of the firing properties of these cells (Fig. 6Ab) revealed that 9 out of 11 were non-bursting elements (RMP =
–67.7 ± 5.1 mV, Ri
= 57.2 ± 14.3 M, APA = 99.2 ± 5.4 mV, APD = 1.2 ± 0.1 ms). Superfusion of these slices with picrotoxin transformed the activity of these ‘silent’ cells into synchronous burst firing (Fig. 6Aa, Picrotoxin). Monitoring the evolution in the intracellular activity of these neurones from the onset of picrotoxin application (Fig. 6Aa, Picrotoxin (transition)) until the complete synchronization between hippocampal areas and EC (Fig. 6Aa, Picrotoxin, late) revealed a gradual decrease in the frequency of occurrence and the eventual disappearance of the robust PSPs (Fig. 6Aa, Picrotoxin (transition) versus Picrotoxin (late)) along with the complete blockade of the isolated hyperpolarizing potentials. As with the other group of subicular cells, the intrinsic firing patterns of these neurones were not changed by picrotoxin (not shown).
Picrotoxin-induced potentiation in subicular activity is not due to upstream effects
It has been well documented that GABAergic circuits exert an important inhibitory control over local networks within CA3/CA1; in addition, loss of this restraint via GABAA receptor antagonism is sufficient to unmask polysynaptic glutamatergic excitation within these structures (Miles & Wong, 1987; Miles et al. 1988). Hence, it can be reasonably argued that the picrotoxin-induced potentiation of subicular activity observed in our experiments might arise from enhanced, upstream hippocampal output rather than decreased gating within the subiculum. In order to clarify this issue, bath application of picrotoxin was investigated in slices in which the subiculum was isolated from CA3/CA1 by knife-cuts to the Schaffer collaterals (Fig. 7Aa). In this set of experiments, potentiation of subicular activity upon GABAA receptor antagonism was observed to occur in spite of the cut (n = 6, Fig. 7Ab, + Picrotoxin). However, epileptiform discharges in this scenario appeared to initiate sometimes in the subiculum (n = 3 slices) and at other times in the EC (n = 3 slices) (Fig. 7Ab, inset).
The potential gating role of subicular networks was further addressed in isolated subicular minislices (Fig. 7B). In the presence of 4AP, low-amplitude synchronous discharges (interval of occurrence = 142 ± 107 s; 55–450 s; n = 18) were observed to occur in all areas of the isolated subiculum and could initiate in the proximal, middle or distal regions (Fig. 7Ba, Control (4AP)). Subsequent addition of picrotoxin induced a drastic augmentation of activity in all subicular regions (n = 13, Fig. 7Ba, + Picrotoxin) thereby providing conclusive evidence that during 4AP application subicular networks, both in the combined slice and the isolated minislice preparations, are under tight GABAA receptor-mediated control.
Slow 4AP-induced interictal discharges generated in the subiculum represent the activity of synchronized interneuronal networks
Intracellular characterization of the slow-interictal discharges recorded in subicular minislices revealed a sequence of an early hyperpolarizing IPSP followed by a long lasting depolarization that could at times trigger action potential firing (Fig. 8Aa and b and B, Control (4AP); n = 20 neurones). Bath application of picrotoxin abolished these events and in their place robust network bursting was observed (n = 6 neurones, Fig. 8Aa, + Picrotoxin).
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Discussion |
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The 4AP model revisited in the light of different patterns of epileptiform activity
We have reported that in reciprocally interconnected hippocampus–EC slices obtained from adult rat (Benini et al. 2003) or mouse brains (Barbarosie & Avoli, 1997; Barbarosie et al. 2000), application of 4AP-containing or Mg2+-free medium induces CA3-driven interictal events that propagate to the EC where they control the propensity of this latter structure to generate ictal discharges resembling those seen in MTLE patients (cf. Swartzwelder et al. 1987; Wilson et al. 1988). Accordingly, cutting the Schaffer collaterals in these functionally connected slices averts CA3 outputs and discloses NMDA receptor-mediated ictal events in the EC, thus leading to a pattern of epileptiform activity similar to what is recorded in functionally disconnected slices (Avoli et al. 1996; Benini et al. 2003).
Until now, we assumed that the inability of CA3-driven interictal activity to propagate to the EC was caused by the slicing procedure that had led to damaging the connections between hippocampus proper and EC. Contrary to this view, we have discovered here that GABAA receptor antagonism can reversibly transform a disconnected slice into one that appears to be functionally connected. Hence, these findings demonstrate that the two patterns of electrographic activity may not reflect anatomical differences, but rather implicate a mechanism that rests on the gating role played by subicular networks on the propagation of epileptiform discharges originating in the hippocampus proper.
Subicular networks gate hippocampal outputs via GABAA receptor-mediated mechanisms in functionally disconnected slices
By using sequential recordings along the CA3–CA1–subiculum axis of functionally disconnected slices we have found that the amplitude of the 4AP-induced interictal activity decreases dramatically in the subiculum, where it is often non-existent. Moreover, during GABAA receptor antagonism, the subiculum undergoes the most dramatic potentiation in field activity (150–550%) signalling an increased recruitment of neurones.
It has been established that disinhibition unmasks polysynaptic excitation within CA3 neuronal networks (Miles & Wong, 1987; Miles et al. 1988) and it is possible that this improved synchronicity would consequently lead to an increased drive onto the subiculum. Local pharmacological activation of the subiculum would have been ideal for clarifying this issue. However, initial attempts at focal applications of picrotoxin were elusive due to the fact that in our horizontal slice preparation the subiculum lies critically close to other structures (CA1, dentate gyrus, and medial EC) and dispersion of the droplet to these areas could not be avoided. This being said, our observations strongly suggest that although increased presynaptic release of excitatory transmitters at CA1–subiculum synapses may occur, this mechanism is unlikely by itself to explain the amplification of subicular activity observed under GABAA receptor antagonism. First, potentiation of subicular activity upon GABAA-receptor antagonism was observed even when the subiculum was separated from CA3/CA1 via microknife cuts to the Schaffer collaterals. Furthermore, significant augmentation in activity was demonstrated to occur in isolated subicular minislices in the absence of either upstream or downstream factors. Altogether this is conclusive evidence that the picrotoxin-induced effect in the subiculum is not due to enhanced output of upstream structures (i.e. CA3/CA1) but rather due to the decreased control of GABAergic circuits within the subiculum itself.
Investigation into the functional role of GABAergic circuits within the subiculum was made possible by the interesting property of the 4AP model used in our study. In addition to blocking K+ currents (Rudy, 1988) and interfering with Ca2+ channels (Segal & Barker, 1986), 4AP has been shown to facilitate neurotransmitter release at presynaptic terminals of both excitatory and inhibitory synapses (Thesleff, 1980; Rutecki et al. 1987; Aram et al. 1991). Previous studies have shown that the subiculum is indeed capable of generating robust interictal discharges under conditions of decreased inhibition (Harris & Stewart, 2001) or increased excitation (Behr & Heineman, 1996; Harris & Stewart, 2001). Using our model we have, however, shown that the subiculum does not generate robust activity when both excitatory and inhibitory mechanisms are simultaneously altered. Furthermore, we found in the isolated subiculum that under such conditions, this structure is more likely to generate slow synchronous events that are resistant to glutamatergic antagonists but sensitive to GABAA receptor blockade. These synchronous potentials, which have been reported in other hippocampal structures as well as in the neocortex, represent the activity of highly synchronized interneuronal networks (Perreault & Avoli, 1989, 1992; Michelson & Wong, 1994; Avoli et al. 1994, 1996; Lamsa & Kaila, 1997). Altogether, these findings indicate that the overall activity of the subiculum in the presence of 4AP is dominated by inhibitory mechanisms that control hippocampal output propagation to the EC. Blockade of GABAA receptors hampers this inhibition (as suggested by the decrease in IPSPs recorded in ‘silent’ subicular cells), allowing an increased recruitment of subicular networks and the consequent spread of both spontaneous and stimulus-induced activity from the hippocampus to the EC.
Subicular cells may be under a different degree of GABAA receptor-mediated control in the same functionally disconnected slice
Neurophysiological investigations have shown that several types of GABAergic cells are present in the subiculum (Kawaguchi & Hama, 1987; Greene & Totterdell, 1997; Menendez de la Prida et al. 2003). We have found here that under control conditions (i.e. during application of medium containing 4AP only) subicular pyramidal neurones generate two different patterns of intracellular activity in functionally disconnected slices: one group of cells fired action potentials in coincidence with CA3-driven interictal events whilst the other generated either EPSP–IPSP sequences or isolated IPSPs. These two behaviours of subicular cells, both of which could be found in the same slice, have also been reported in the human epileptic subiculum of MTLE patients, where they reflect differences in the reversal potential of pyramidal cells for GABAA receptor-mediated conductances (Cohen et al. 2002).
The presence of ‘silent’ subicular cells in functionally disconnected slices indicates that hippocampal activity may not propagate to the EC due to local inhibitory control exerted on a subset of projecting subicular cells. In line with this view, previous studies have demonstrated that subicular pyramidal cells are restrained by local GABAergic networks via feedforward (Finch & Babb, 1980; Colino & De Molina, 1986; Finch et al. 1988; Behr et al. 1998) and recurrent inhibitory mechanisms (Menendez de la Prida, 2003; Menendez de la Prida & Gal, 2004). Accordingly, we have demonstrated that IPSP blockade by GABAA receptor antagonism coincides with the appearance of network-driven burst firing, thus implicating a role for subicular GABAA receptor-mediated inhibition in gating hippocampal output activity. Indeed, it has been reported that epileptiform discharges generated in the hippocampus can successfully propagate to the medial EC via the subicular complex under reduction of GABAergic mechanisms (Menendez de la Prida & Pozo, 2002).
Conclusions
Studies in various epilepsy models have identified the dentate gyrus as a gater for the spread of limbic seizures from the EC to the hippocampus proper (Collins et al. 1983; Heinemann et al. 1992). However, until this study, no investigation had addressed the role of the subiculum in controlling hippocampal outputs during epileptiform synchronization even though it was well established that this structure is in a strategic position for doing so. Our observations that blocking GABAA receptor-mediated mechanisms results in subicular hyperexcitability and subsequently intralimbic synchronization is relevant to pathological conditions such as epilepsy. Studies in slices obtained from MTLE patients indicate that both bursting pyramidal cells and interneurones contribute to the interictal activity that occurs in the subiculum (Cohen et al. 2002; Wozny et al. 2003). In addition, in chronic animal models of MTLE, alterations at the level of intrinsic and network properties of principal cells (Wellmer et al. 2002; Knopp et al. 2005) as well as a reduction in specific interneuronal subpopulations (van Vliet et al. 2004) have been reported in this structure. Altogether, these findings suggest that synaptic reorganization and altered inhibition contribute to subicular network hyperexcitability that may in turn play a role in the generation and spread of convulsive activity.
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