Cellular electrophysiology of human epilepsy

EPILEPSY RESEARCH

ELSEVIER Epilepsy Research 17 (1994) 1X5--192

Review Article

Cellular electrophysiology of human epilepsy

Philip A. Schwartzkroin*

Abstract

The electrophysiological characteristics of neurons in human epileptic tissue are reviewed, with emphasis on experiments employing in vitro slice analysis of human neocortex and hippocampus. There is little evidence for an alteration in intrinsic properties of cortical or hippocampal neurons in human epileptic tissue, However. data support some decrease in functional i~lhibition and/or increase in synaptic excitation. In stices from epileptic brain. bursting discharge can be evoked under conditions that do not elicit such discharge patterns in normal animal tissue. h/lost bursts are generated from prolonged and/or enhanced EPSPs; spontaneous bursting activity, and all-or-none discharge (i.e., paroxysmal depolarizations) are rarely seen in vitro. Underlying structural alterations have been correlated with increased excitability, but cause/effect relationships have not been established. These data suggest that a variety of mechanisms may contribute to epileptogenicity in human cortical tissues.

KC,Y tsorch: Cortex; Hippocampus; Hyperexcitabiiity; IPSPs: NMDA: Sprouting

1. Introduction

Although the study of cellular activities in the human epileptic brain constitutes a relatively young field of endeavor, it does have a history. In 1955, Ward and Thomas [.59] described the extra- cellularly recorded activity of neocortical neurons

in a human patient undergoing surgery to resect an epileptic focus. The Ward group [10.64] subse- quently reported on the burst discharge patterns that characterized the epileptic neocortex. In their unanesthetized patients, they found that cell discharge was only weakly correlated with the occur- rence of surface-recorded interictal EEG spikes,

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and that there was a considerable degree of cell to cell variability; cell synchronization increased, however, as the seizure was initiated. Babb and

colleagues expanded this description. showing that a relatively small proportion of cells fire in co~ljunction with interictal EEG spikes [5.9]; although more cells are ‘recruited’ during transi- tion to seizure. not all cells participate even during ictal activity. These studies provided important basic information about cellular activities associated with epileptic events in human brain, espe- cially since these patterns are somewhat different from the highly synchronized characteristics of discharge in acute experimental animal models. However, these extracellular recordings were primarily descriptive, and thus provided little insight into the underlying basis of the epileptic activities.

Intracellularly recorded activities associated with epileptiform events could not be obtained consis- tently in vivo from human brains. Some hope of obtaining additional understanding, through the intracellular window. filtered into the field with the introduction of the in vitro slice preparation [25.45,65].

In 1976, Schwartzkroin and Prince [50] reported on the first intracellular in vitro recordings

from human epileptic cortical tissue. Since that

time. a number of laboratories have investigated the underlying epileptogenic mechanisms of human epileptic brain using this in vitro tool [47]. Much of the in vitro analysis depends, of course, on comparing cell properties from ‘epileptic’ brain samples with cell properties from ‘normal’ control

tissue. There has been much discussion about what constitutes an appropriate control in such experiments, and the problem has not been re- solved. Every laboratory has its own way of deal- ing with the issue, but none of these ‘solutions’ is

perfect or universally accepted. The problem of appropriate controls is an important one, and must be addressed in any study of cellular epilep-

togenic mechanisms in human tissue. If one defines ‘epileptic activity’ as abnormal

electrical discharge, characterized by hypersyn- chrony and/or hyperexcitability. then the epilepto-

genicity of resected human tissue neocortex or hippocampus ~ has not been immediately obvious in most reported in vitro studies. In those tissue

samples, there is little sign of spontaneous epileptiform events that would guide an investigator in his/her search for underlying cellular mechanisms. Experimenters have therefore adopted a number of different strategies in studying the tissue from human epileptic brain. In general, two rather

broad hypotheses have been tested: first, that intrinsic properties of neurons in epileptic brain are somehow altered; and second, that synaptic com- munication among cellular elements is abnormal.

2. Intrinsic cell properties

In our initial studies of neocortical and hippocampal tissues [49-511, we found that the intrinsic properties of presumed pyramidal cells were

grossly similar to pyramidal cell properties described for rat, cat, and monkey (see also refs. 26, 57). That is. such measures as cell resting potential, input resistance, and action potential proper-

ties were much as expected from previous work on experimental animal preparations. To some ex-

tent. such findings represent self-fulfilling prophe- cies, since selection criteria for acceptable intracellular impalements tend to ‘discard’ cells with properties that fall outside the expected ranges. For

example, although we reported that some neocortical cells from within an interictally discharging

region generated ‘fractionated’ spikes [46] a fea- ture not seen in normal pyramidal cells we were never confident that this observation reflected tissue epileptogenicity, and were inclined to disre- gard such a phenomenon as a function of electrode-induced injury.

As indicated above, defining cell features associated with tissue epileptogenicity requires comparing ‘epileptic’ tissue with comparable normal control tissue. While some recent studies have at-

tempted to survey and compare tissue taken from the midst of an epileptogenic region with tissue from relatively normal cortex (from the same

brain), other investigators have been satisfied to compare human neuronal characteristics to cell properties established in studies of normal animal

cortex and hippocampus. The studies by Knowles et al. [26], Foehring and colleagues [16,2X]. and Avoli and Olivier [2] generally confirm that intrinsic cell properties in human epileptic tissue samples fall within the ‘normal’ range for pyramidal cells (resting potential. input resistance, time con- stants. action potentials, spike after-hyperpolari- zations (AHPs), burst AHPs, etc.). Investigators have had very little success in differentiating cells from epileptic versus non-epileptic tissues on the basis of these intrinsic properties. Foehring et al. [ 171. however, have shown that morphologically distinct cell types in human neocortex have distin- guishable discharge patterns; they attributed these differences to different subsets of calcium channels. Using an acutely dissociated cell preparation, Sayer et al. [44] have been able to apply whole cell patch clamp techniques to investigate the nature of calcium currents in human neurons. Their studies. too. have revealed that human neu-

P.A. Scl2,~art-kroin!Epilep.v? Research I7 i 1994 i l(IS--192 187

rons behave much like comparable cells in non- human animal neocortex, with both low thresh-

old (T-type) and high threshold (L- and N-type) calcium currents.

Many of the cellular studies of human epileptic tissue have concentrated on the nature of synaptic events. Toward this end, investigators have exam- ined the effects of various transmitter substances on neurons from purportedly normal neocortical tissue resected during epilepsy surgeries. For example, McCormick [33] has shown that inhibitory

postsynaptic potentials (IPSPs) in human neocortex have both GABAA and GABAn components, and that these potentials have ionic and pharma-

cologic characteristics similar to those found in cells described in animal experiments. This labora-

tory group also has reported that acetylcholine, adenosine, GABA, histamine, norepinephrine, and serotonin all can exert effects through potas- sium channels ~ consistent with results found in studies of non-human cortical cells [34].

In most of the laboratories investigating human tissue, the work has focused on comparing cells from ‘epileptic’ and ‘normal’ tissue, addressing the following four questions: (a) Is there a reduction of inhibition in epileptic

tissue? (b) Are cells in epileptic tissue more prone to burst in response to stimulation? (c) Is there an exaggerated contribution of NMDA-mediated currents to the excitatory PSPs (EPSPs) and/or bursts of cells in epileptic tissue? (d) How is ‘sprouting’ correlated with increased excitability?

3.1. IPSPs in human epileptic tissue There is now little question that IPSPs can be

recorded from neurons in ‘epileptic’ neocortex and hippocampus [2,26,49,5 I ,55,57]. Anatomical/immunocytochemical studies have shown that GA- BAergic cells are not selectively lost (and may even be preferentially preserved) [8]. In vivo cellular electrophysiological recordings [24] even suggest that inhibition may be enhanced in epileptic

temporal lobe. In vitro studies have all confirmed

the presence of IPSPs, in cortex and hippocampus, in tissue closely associated with EEG spike discharge as well as in presumably ‘non-epileptic’ tis-

sue [3,49,51]. In our early studies, we found that the number of cells exhibiting clear IPSPs was somewhat reduced in ‘epileptic’ cortical samples

as compared to relatively normal controls. More recently, Knowles et al. [27] have reported that

fewer cells in sclerotic hippocampus show IPSP activity than in epileptic hippocampus associated

with a gross structural lesion, and that the cells from sclerotic hippocampus are more burst- prone. That GABAergic IPSPs are present and play a role in controlling excitability, even in epi-

leptic tissue, is also suggested by the demonstration that application of bicuculline ~ a specific GABA* blocker ~ increases cell excitability and leads to burst discharge. This phenomenon, studied for so long in animal models, has been

shown for human epileptic neocortex [21], hippocampus [40], and tissue from immature brain [54]. We have also described the presence of sponta-

neous, rhythmic, synaptic events in both cortical and hippocampal epileptic slices [48]. Since these events appear to be GABA-mediated (they are

blocked by bicuculline), their existence suggests that the GABA circuitry is not only intact, but can also generate synchronized activity within

this tissue. Such a role for the GABA circuitry has recently been shown in experimental animal preparations [36]. These results, combined with the immunocytochemical evidence of persistent

GABAergic neurons and terminals, indicate that the epileptic human brain contains the necessary machinery for mediating inhibition. What is not clear is: whether the GABA machinery is normally functional (a number of recent animal model studies support the idea of a ‘dormant’ or ‘func- tionally disconnected’ inhibitory circuitry); and whether small reductions in IPSP efficacy occur in human epileptic brain (as suggested in experimental animal slice studies, where a calculated reduction of inhibition as small as 15% was shown to induce hyperexcitability of neocortical tissue

1121).

3. Synaptic activities

In studies of both neocortical and hippocampal

tissue from human epileptic brain, investigators have reported that a proportion of neurons show

an ‘abnormal’ tendency to discharge in burst patterns. That is. when aetivated by afferent input,

the cells fire in bursts of action potentials rather than the single spike mode more typical of normal pyramidal (and hippocampal granule) cells. Studying neocortical epileptogenic tissue, Prince and Wong [41] initially reported burst activity associated most closely with structural malforma- tions; that association has apparently been con-

firmed by Strowbridge et al. [53]. The most common burst form appears to derive from an exag- geration and prolongation of a normal excitatory

synaptic drive, with the length of the burst a function of the intensity of the stimulation. Occasion- ally, all-or-none paroxysmal bursts have also been

recorded, and recent studies have described spontaneous burst activity in some cortical tissues [59]. In studies of hippocampus. we have also found stimulus-dependent and all-or-none burst types. with the former discharge pattern being much more common. Masukawa et al. [31] have de-

scribed burst discharge in human epileptic hippo- campai neurons when the tissue was stimulated

repetitively at low frequency (1 .O Hz). This phenomenon is similar to that seen in normal animal tissue perfused with low concentrations of bicucul-

line, suggesting that a minimal compromise of the GABAergic inhibitory system in human epileptic tissue might be responsible for at least some epileptiform activities.

Studies of both neocortical and hippoc~~mpa~

tissue have reported NMDA invoivement, both in apparently normal synaptic activities, and also in epileptiform discharge [I ,22,30,40,58]. In studies of human neocortical slices from epileptic patients, Avoli et al. [4] showed that seizure-like discharge could be evoked by lowering the magnesium concentration of the bathing medium, thus presumably ‘activating’ NMDA-mediated synaptic function which is normaliy blocked by higher

~li~~gnesiurn levels. Not surprisingIy, thcsc mvcstt-

gators found NMDA receptor antagonists (APV, CPP. MK-80 1) effectively blocked this low magno- sium-induced burst discharge: the non-NMDA al?t~~gonist. CNQX failed to alter the freyucncy ctt these events 1.31. This same group of investigators [Zl] have also shown that NMDA antagonists can block bicuculline-evoked and stimulus-evoked burst discharges in human ncocortical slices. WiI- liamson et al. 1601 have found that APV (but not CNQX) reduces the frequency of spontaneously occurring burst discharges from tissue associated with structuraf lesions of the cortex. Dudek and colleagues [63] have carried our voltage clamp studies of synaptic responses in neocortical neurons in tissue resected from children with intractable epilepsy, and described a significant NMDA com-

ponent in the EPSP. The properties of this NMDA contribution (e.g., its voltage dependence) appear similar to those reported for nor-

mal mammalian cortical neurons; that is, NMDA function did not appear to be different in this immature epileptic tissue.

In sum, although several studies have detailed an NMDA contribution to excitatory synaptic events in human neocortical tissue, it remains un- clear if NMDA activation contributes directly to tissue epileptogenicity, or whether the level of the NMDA contribution is different in epileptic versus normal tissue. It is of considerable interest. therefore, that Louvel et al. 1291 have found an apparently altered distribution of NMDA respon- sivity in neocortical slices from epileptic patients.

In man, as in other mammals, NMDA receptors are normally concentrated in the upper layers of neocortex [3x]. in epileptic cortical slices, however. the region of NMDA sensitivity was found to be much broader, spanning most of the cortical layers. Thus, an ~&bn(~rl~~~l NMDA receptor distribution may indeed contribute to cortical epi-

leptic discharge. In hippocampus, several laboratories have re-

ported a significant NMDA contribution to excitatory synaptic events [22,30,40,58]. These investigators have found a significant NMDA component to the dentate granule cell EPSP and/or burst discharge, primarily as determined by the blocking action of APV. These data appear to be

signi~~ant for tissue epilept~genicity, since in the normal rat granule cells there is little NMDA con-

tribution to this EPSP; further, studies by Mody et al. 1371 have shown that an NMDA contribution develops in these cells when the rat is kindled. Clearly, the observation of an NMDA component in the human granule cell EPSP is intriguing - but still difficult to interpret without comparable data from ‘normal’ human granule cells. Receptor binding studies on hippocampus of epileptic patients add to the confusion regarding the relative importance of NMDA receptors in epiieptiform activities, since different laboratories have reported almost opposing results when looking for changes in this glutamate receptor subtype [19,35]. Investigators have also reported an increase in non-NMDA (i.e., AMPA) binding [19], and in kainate binding in tissue from immature hippocampus [42]. Thus, there are some sugges- tions of changes in excitatory amino acid receptor distribution in epileptic brain, but the data are not clear or consistent. It is certainly impossible to determine whether such changes represent a result of, or ~ontributin& cause to, the subnormal (i.e.. epileptic) activity.

‘sprouting’ of mossy fibers into the inner molecular layer of the dentate gyrus of epileptic human hippoc~~mpus [6,7,20,23.54]. Experimental animal studies have shown similar morphological changes. and a number of groups have tried to correlate this structural plasticity with an alteration in excitability [ 1 1,13,14,56]; there is, however, some controversy over the question of whether such sprouting is causally related to increased excitability [.52]. Masukawa et ai. (32f have recently reported that the degree of excitability as as- sessed by antidromicaily induced multiple popula- tion responses in the granule cell layer of human epileptic hippocampal slices -- is correlated with the extent of mossy fiber sprouting (as seen in Timm staining). Similarly, Pokornp et al. [40] have shown that cellular bursting activity in human epileptic hippo~a~lpus is correlated with the demonstration of mossy fiber sprouting. In this

latter study, intra~eilu~ar 1abeIling of impaled granule cells revealed a substantial axonal ramifi- cation in the dentate inner molecular layer in some - but not all - epileptic tissue samples (see also ref. 23). Given that mossy fiber synapses are associated with kainate receptors in normal hippocampus [39], it is interesting to note that receptor binding studies have shown an increase in kainate binding precisely in the inner molecular Iayer of the dentate of epileptic hippocampus [42]. It is also important to note that increased excitability associated with the mossy tibcr sprouting is not immediately apparent in in vitro studies, but requires some compromise of the inhibitory system of these tissue slices (either bicuculline treatment or repetitive stimulation).

4. Conclusions

How can we summarize these diverse data, and what do they mean for our understanding of the cellular bases of epileptogenesis? Although none of these studies has provided clear answers, there have been an increasing number of important observations that give us some insight into the tissue epileptogenicity. I would summarize the most sali- ent observations as follows. First, despite the morphological evidence that GABAergic cells remain intact, there is evidence that inhibitory efficacy may be compromised in human epileptic tissue. Even a slightly disinhibited state may have important consequences. That such may be the case is reflected in the reports of a reduced frequency of IPSPs, and the sensitivity of excised tissue to low doses of GABAA blockers or to low frequency repetitive stimulation; in normal tissue, these treatments are relatively benign, but in epileptic tissue, they lead to burst discharge. Second, there is also evidence that excitatory amino acid- mediated EPSPs may be altered in epileptic tissue. NMDA contributions to normal and epileptiform activities have been demonstrated and changes in both NMDA and non-NMDA receptor populations have been reported. Third, cellular burst discharge patterns do appear, and can be elicited, in epileptic tissues. As in chronic animal models, and as shown in in vivo extracellular re-

cordings from epileptic brain. not all cells burst; a relatively small percentage of relatively synchro-

nized neurons may constitute the critical driving force needed for generation of epileptiform events. Cell burst discharge generally takes the

form of prolonged EPSPs (not paroxysmal depo- larization shifts), and may result from reduced in-

hibition, enhanced excitation, or ~ more likely - a combination of both.

Clearly, a great number of potential underlying mechanisms may contribute to this epileptic state. We have become significantly more sophisticated about how to view such mechanisms, and many

laboratories now have the opportunity to apply electrophysioIogic tools to the study of tissue from epilepsy surgeries. The in vitro studies on which this review has concentrated are not the

only productive neurophysiologic approaches for studying basic mechanisms of the epilepsies. Re- cording and stimulation studies in the intact human brain [43,61,62] are critical if we are to put

these cellular insights into context. Other approaches, both conventional and novel, are all needed. New technologies, such as optical imaging [18] and in situ microdialysis [I 51, may pro- vide important new information to help interpret

basic electrophysiologic and morphologic data. Finally, animal experimentation continues to be critical ~ for developing and testing hypotheses - in any effort to understand the neurophysio~ogic

bases of the epifepsies.

5. Acknowledgement

This review is adapted from a lecture presented at the American Epilepsy Society Annual Meeting, December 7, 1992, Seattle, WA.

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Cellular electrophysiology of human epilepsy