Chapter 22 Electrophysiological substrates for focal epilepsies

O.P. Ottersen, LA. Langmoen and L. Gjerstad (Eds.) Progress in Brain Research, Vol 116 0 1998 Elsevier Science BV. All rights reserved.

CHAPTER 22

Electrophysiological substrates for focal epilepsies John G.R Jefferys” and Roger D. Traub Neuroscience Unit, Department of Physiology, The Medical School, University of Birmingham, Vincent Drive, Edgbaston. Birmingham B15 2TT, U K

Glutamate plays a central role in the neuronal circuitry that recruits neurons into epileptic discharges. In the hippocampal CA3 region glutamatergic synapses between pyramidal cells provide the substrate for a chain reaction which leads to the synchronous epileptic discharge. Both AMPA and NMDA receptors are present at these recurrent synapses; AMPA receptors are responsible for the synchronization of epileptic bursts in the bicuculline/picrotoxin models and NMDA in the low-Mg2+ model. The slower kinetics of NMDA receptors can prolong discharges from the 100 ms of the interictal spike to the first few hundred ms of an afterdischarge. Events lasting as long as a full seizure ( > 10’s of seconds) can occur in several experimental epilepsies in the slice. Seizure-like events in the bicuculline model are not sensitive to NMDA receptor antagonists; they may be due to spontaneous release of glutamate from presynaptic terminals and/or activation of metabotropic glutamate receptors.

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Glutamate’s role in epilepsy

Amongst the earliest uses of the selective glutamate antagonists that became available during the 1970’s was the dissection of their anticonvulsant *Corresponding author. Tel.: +44 121 414 7629. 7525; fax: +44 121 414 7625; e-mail: [email protected].

actions. Around the same time it became clear that glutamate could kill neurons through “excitotoxicity” (Choi, 1995) (Mody and MacDonald, 1995) (Olney et al., 1986) (Simon et al., 1986). More recently it has been shown explicitly that glutamate is released during epileptic discharges (During and Spencer, 1993). We will briefly outline evidence from these sources that glutamate receptors play a crucial role in epilepsy, before discussing in more detail what that role might be in the context of the synchronization of local networks of neurons. A critical step forward in this story was the development of agonists and antagonists to the various glutamate receptors, largely by the group of J.C. Watkins. As is made clear elsewhere in this volume, (seeaorges and Dingledine; Monaghan, this volume) the major ligand gated channels that concern us here are called AMPA and NMDA after their selective agonists. The third major class of glutamate-gated ion channel is the kainate receptor. We will also mention metabotropic glutamate receptors (mGluRs) which are the Gprotein coupled class of glutamate receptor (see Bruno et al., this volume). It quickly became clear that NMDA and kainate agonists resembled glutamate itself in being convulsant and also toxic to neurons (Ben-Ari et al., 1980). NMDA receptor antagonists proved effective anticonvulsants in several animal models in vivo, and protected against neuronal loss induced by seizures (and

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ischaemia) (Coutinho-Netto et al., 1981; Croucher et al., 1982; Meldrum, 1994). NMDA receptor antagonists were also able to block the development of kindling, but not its expression in animals kindled previously (Callaghan and Schwark, 1980; Croucher et al., 1988). Kindling is a chronic model of epilepsy in which repetition of initially subconvulsive stimulation lead to a reduction in seizure threshold and increase in seizure severity which lasts indefinitely. Analogous results have been found in models in vitro too (Stasheff et al., 1989). The fact that it was the induction phase that was selectively blocked by NMDA antagonists suggested that the kindling process itself depended on plastic synaptic changes analogous to those in long term potentiation (LTP) (Bliss and Collingridge, 1993), but that the final expression more likely depended on AMPA receptors (again this has parallels with LTP). The release of glutamate during seizures can kill neurons, mainly as a result of Ca2+ entering with the Nat and K f through the NMDA receptor and through certain kinds of AMPA receptor (those which lack the GluR-B subunit) (Bochet et al., 1994; Jonas et al., 1994). The anticonvulsant, antiepileptic and neuroprotective roles of NMDA receptor antagonists made them promising novel drugs for the treatment of epilepsy and some kinds of brain injury (see Chapman; Tauberll and Gjerstad, this volume). Unfortunately adverse side effects of these drugs have so far prevented their translation into the clinic.

experimental models had shown that neurons appeared electrically normal until they suddenly became recruited into an epileptic discharge; they experienced a so-called “paroxysmal depolarization shift” (PDS) synchronously with each other (and consequently with the extracellular field potential discharge). A key step forward was the adoption of the brain slice preparation by electrophysiologists,and the recognition that several epilepsy models worked in vitro. Early on it was recognised that drugs that blocked inhibition (e.g. penicillin (Dingledine and Gjerstad, 1979), bicuculline and picrotoxin) produced epileptic discharges in hippocampal and neocortical slices (Dingledine and Gjerstad, 1979; Wong and Traub, 1983; Gutnick et al., 1982). In the hippocampus most kinds of epileptic discharge start amongst the pyramidal cells of the CA3 region (Gjerstad et al., 1981; Wong and Traub, 1983; Gutnick et al., 1982). In a critical experiment Johnston and Brown (1981) showed that the PDS in CA3 pyramidal neurons had the properties of a giant EPSP, in that both PDS and EPSP reversed at the same membrane potential. They also showed that the PDS continued at the same rate when the impaled neuron had been hyperpolarized sufficiently to stop its firing, which lent strong support to the idea that the PDS was a property of the network rather than of individual neurons.

Basic mechanisms of epilepsies

At that stage it was not clear how the giant EPSP could come about. Two properties of CA3 pyramidal neurons seemed potentially important. Firstly, they could fire complex spikes due to the presence of voltage-sensitive calcium channels (Wong and Prince, 1981; Schwartzkroin and Slawsky, 1977) (for a more detailed model of CA3 pyramidal cells see (Traub et al., 1994a)). Secondly, they were joined by monosynaptic excitatory connections, albeit at a relatively low probability of -2% (MacVicar and Dudek, 1980; Miles et al., 1984; Miles and Wong, 1987). It took another technical advance to show whether this

While glutamatergic drugs so far have failed to live up to their initial promise, they have been a major asset in attempting to unravel the basic mechanisms of epileptic activity. The central question is why should large numbers of neurons abruptly start to discharge synchronously to produce the epileptic seizure. Much of the work in this area has concentrated on brief synchronous events which last about 100 ms, and which resemble interictal spikes on EEGs from patients with focal epilepsies. Early electrophysiological studies of a number of

Neuronal circuits for epileptogenesis

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low level of connectivity was necessary and sufficient to explain the epileptic synchronization and the PDS. That advance was the development of realistic computer models of real CA3 pyramidal neurons and their assembly into synaptic networks. These models showed that the network of excitatory synapses between pyramidal neurons provides the substrate for the build-up of excitation and synchrony (Traub and Wong, 1982; Traub and Miles, 1991). Epileptic discharges occur: (a) if neurons are connected by divergent, excitatory synaptic connections; (b) if these synapses a strong enough to excite the postsynaptic neurons with a reasonable probability (Miles and Wong, 1987); and (c) if the population of neurons is large enough (the “minimum aggregate”, 100&2000 CA3 pyramidal neurons in disinhibited slice and in computer models with spatially structured synaptic connectivity (Miles et al., 1984)). This scheme works for a diverse range of experimental models. Conditions a and c are determined by anatomy, but may change in chronic epilepsies. Condition b depends on: the properties of the synapses between pyramidal cells, the operation of inhibitory neurons, and the intrinsic properties of pyramidal cells. Voltage sensitive calcium currents play a key role in amplifying excitation through the CA3 pyramidal cell network in several models (Traub and Wong, 1982; Traub and Miles, 1991). Persistent sodium currents result from a non-inactivating state of the tetrodotoxin sensitive sodium channel. Its low threshold and persistence allows it to amplify EPSPs (Crill, 1996; Schwindt and Crill, 1995) and thus can contribute to epileptogenesis by amplifying condition (b) above (Segal and Douglas, 1997). Under some conditions persistent sodium currents can underlie intrinsic neuronal bursts, for instance in pyramidal cells of the neocortex and subiculum (Tian et al., 1995), much as calcium currents do in CA3 (Traub and Wong, 1982; Traub and Miles, 1991). The vast majority of fast excitatory synapses in the brain are glutamatergic. Those made by CA3 pyramidal neurons are no exception. They appear to use both AMPA (non-NMDA) and NMDA

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receptors. The presence of AMPA receptors at the recurrent synapses explains why antagonists to AMPA, and not to NMDA, receptors block epileptic discharges induced by blocking synaptic inhibition (Traub et al., 1993) (e.g. with bicuculline or picrotoxin), or by blocking certain potassium channels (with 4-aminopyridine) (Traub et al., 1995). In contrast, antagonists at NMDA, and not AMPA, receptors block epileptic activity induced by removing magnesium ions from the bathing medium. This model-specific pharmacology, and our computer simulation studies argue that the recurrent synapses between CA3 pyramidal cells must use both AMPA and NMDA receptors, although we cannot distinguish whether these receptors are colocalized at the same synapses or whether they occur in different subsets of these synapses. Selective kainate receptor ligands are a relatively recent development. They suggest that kainate receptors in the CA3 region are activated by the mossy fibre (granule cell axon) input from the dentate area and not by synapses made by pyramidal cells (Vignes and Collingridge, 1997). Therefore kainate receptors will not play a role in the initiation of epileptic activity in CA3, but they could play a role in vivo when seizures spread through the limbic system, and CA3 will receive excitation from the entorhinal cortex through the mossy fibres. Magnesium ions block, in a voltage-dependent manner, NMDA receptors under physiological conditions (and also in the bicuculline and 4aminopyridine models). The removal of Mg2+ leads to a considerable strengthening of the recurrent synapses in CA3, because of the increase in the NMDA receptor current, and this leads to epileptic synchronisation (Traub et al., 1994b). (NMDA receptor desensitization contributes to the termination of the epileptic discharge.) This could be important in the rare instances of seizures induced by Mg2+ deficiency, but also has wider significance, given the prominent role of NMDA receptors in chronically epileptic tissue, e.g. in kainate-lesioned and kindled hippocampus (Martin et al., 1992; Kraus et al., 1994; Kohr and Mody, 1994; Mody and Heinemann, 1987; Mody

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et al., 1988) and in human epileptogenic tissue (Masukawa et al., 1991). While the main content of this review relates to the hippocampus, we note that similar principles apply in other brain regions prone to focal epilepsies, including the neocortex, entorhinal cortex and the piriform cortex (Wadman and Gutnick, 1993; Haberly and Sutula, 1992; Lee and Hablitz, 1991; Jones and Lambert, 1990; ChagnacAmitai and Connors, 1989; Gutnick et al., 1982). The detailed connectivity and intrinsic neuronal properties differ between these different regions, but in each the key factor in epileptogenesis is the recruitment of neurons into synchronous discharges through glutamatergic synaptic networks. Glutamate in prolonged epileptic bursts

NMDA receptors have slower kinetics than AMPA. In the picrotoxin/bicuculline model they are required to extend the brief ( ~ 1 0 0ms) interictal burst to the several hundreds of ms of an afterdischarge or polyspike (Traub et al., 1993; Traub et al., 1993) (Fig. 1). We developed a theory of these longer bursts of epileptic activity (Traub et al., 1993). It depends on the following. An initial AMPA receptor-dependent “primary” burst starts the event 0. The glutamate released also activates NMDA receptors. If the activation of NMDA receptors is strong enough, the inward current they generate 0 can eventually counterbalance the outward potassium currents of the intrinsic afterhyperpolarization or AHP that normally terminate the interictal burst. When the inward current through the NMDA receptor exceeds the outward current through the potassium channels of the AHP pyramidal cells start to fire and initiate a “secondary burst”. The activity of neuronal population is synchronized into the secondary burst through AMPA receptors @, so that if some pyramidal cells start to fire a secondary bursts before the others, AMPA receptor mediated EPSPs from the leading cells will advance the phase of secondary bursts in connected cells. The glutamate released during this process also re-activates the NMDA receptors and pro-

longs the slow depolarization @. Calcium channels open as a result of the depolarization and contribute to the depolarization of the secondary burst 0.Calcium entry and depolarization activate the AHP which terminates the secondary burst, and the cycle continues. Another way of looking at this process is that the persistent NMDA receptormediated excitation, in neurons throughout the population, activates a system of coupled neuronal oscillators dependent on intrinsic dendritic membrane currents which determines the shape and frequency of secondary bursts which comprise the late phase of this discharge. Currents through AMPA-type glutamate receptors at recurrent synapses synchronize both the initiation of the discharge, when they must be effective enough to initiate firing in connected neurons, and the phase locking of the secondary bursts across the population of neurons, when their effect is only to influence the timing of each other’s firing (Traub et al., 1993). In principle other slow excitatory mechanisms could operate to play the role of NMDA receptors, such as accumulation of extracellular potassium ions or the activation of slow excitatory synapses. Pharmacological experiments show that NMDA receptors play this role in models where GABA-ergic synaptic inhibition is blocked. Focal epileptic seizures last tens of seconds up to a few minutes. Epilepsy models in slices mostly produce much briefer synchronous discharges. This supported the contention that seizures needed larger amounts of brain tissue, and perhaps several discrete regions joined by long-range projections (Lothman, 1994). While it is clear that many structures become involved in limbic seizures, evidence that seizures depend on activity cycling around a long “re-entrant” loop remains weak. In particular, where phase lags have been measured during seizures, most often there is no consistent lag between regions that might be expected to take part in such loops (De Curtis et al., 1994; Bragin et al., 1997). Evidence from brain slices now suggests that several brain regions can sustain events lasting as long as a seizure, and we believe that seizures in vivo are much more likely to

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represent the interaction of separate regions each of which can sustain seizure-like discharges. In this model seizures do not have to circulate through long loops, but rather they synchronize between regions with low average phase lag, because the “lead” region can fluctuate back and forth from cycle to cycle. Several groups have identified seizure-like or “ictaform” events in brain slices (Korn et al., 1987) (Swartzwelder et al., 1987)‘(Andersonet al., 1986). Some of these resemble low-Ca2+ field bursts, in that they have negative fields and they preferentially start in CA1 within the hippocampus. These kinds of prolonged burst depend in large part on non-synaptic synchronization (through field effects, fluctuations in extracellular ion concentrations and electrotonic junctions) (Jefferys, 1995). Other kinds of seizure-like event more closely resemble discharges we and others have recorded in vivo. For instance, slices of ventral hippocampus exposed to bicuculline produced epileptic discharges lasting up to 1.5 minutes (Traub et al., 1996), especially if the extracellular K f concentration is increased from 3 to 6 mM. These bursts start in the same way as the afterdischarge described above - a primary, AMPA receptor-

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dependent burst followed by a train of NMDA receptor-dependent secondary bursts at 10 per second. These are followed by tertiary bursts at 13 per second. The tertiary bursts are not blocked by NMDA receptor antagonists. Rather they look like a very rapid train of interictal discharges joined by an increase in the spontaneous release of glutamate from terminals. This asynchronous release has the effect of shifting the network into a more excitable state for the duration of the seizure-like event (Traub et al., 1996). Spontaneous synaptic release certainly occurs in the brain, and can be modulated by neuronal activity (Strowbridge and Schwartzkroin, 1996). In at least some cases the asynchronous synaptic activity is evoked by “ectopic” action potentials that can arise spontaneously from axons. Ectopic action potentials were first described in the thalamocortical relay neurons during cortical focal discharges by Gutnick and Prince (1972). Subsequently they have also been reported in other cortical models and in hippocampus during epileptic activity induced by 4-aminopyridine and by tetanic stimulation (Stasheff et al., 1993; Traub et al., 1995; Pinault, 1995). Finally,“metabotropic” glutamate receptors (mGluRs) have recently been shown to modify

,,,@ ,-

4

@initiation exc. network AMPA

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4

@ sychronization @termination exc. network

AMPA

D0mmY( 25mV

(GABA; AHP; NMDA-R

desensitization)

Fig. 1. Intracellular recording from a CA3 pyramidal cell (upper trace) and a simultaneous field potential recording from an adjacent part of the pyramidal cell layer (lower trace) made during a spontaneous epileptic discharge in a rat hippocampal slice exposed to 20 pM bicuculline. Labels cross reference with the text.

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the frequency of epileptic discharges in hippocampal slices in which synaptic inhibition had been blocked by picrotoxin (Merlin et al., 1995). In particular, mGluR agonists can transform interictal bursts into synchronous epileptic discharges, at rates of -10-20 Hz, and lasting many seconds (Taylor et al., 1995).With group I mGluR agonists such as (S)-3-hydroxyphenylglycine, this effect lasts for many hours after the removal of the agonist, which suggests a long lasting potentiation of mGluRs that can then be activated by glutamate released during the epileptic discharges. Human epileptic foci

The value of the work described above on animal tissues, mostly studied in vitro, depends largely on what it can tell us about the human disease. Brain slices can be prepared from tissue removed from humans in the course of surgery for medically intractable epilepsy (Berg-Johnson et al., this volume). On the whole the results from such work have not shown that any one experimental model embodies the human condition. Overall these studies show that there are: modest changes in the kinetics of membrane currents in neurons from these slices, a reduction in synaptic inhibition, and, of particular interest for this review, an increase in the strength and duration of synaptic excitation (see review (Schwartzkroin, 1994)). Given that these changes mostly are small in relation with those found in acute models of epilepsy, it is likely that epileptogenesis results from several underlying biophysical and structural changes, including changes in EPSPs that tend to make them larger, more prolonged, or more likely to be sustained during prolonged discharges. Thus it is likely that glutamatergic transmission, in combination with other factors, plays a significant role in human epileptogenesis. Conclusion

Glutamate plays keys roles in several distinct aspects of epileptic activity. What these roles are

depend on the kind of experimental (and perhaps clinical) epilepsy. Discriminating them from the physiological functions of glutamatergic transmission in order to develop novel therapies remains a major challenge. Acknowledgements

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