Brain, Vol. 122, No. 6, 1009-1016,
June 1999
© 1999 Oxford University Press
Forebrain ischaemia with CA1 cell loss impairs epileptogenesis in the tetanus toxin limbic seizure model
1 University of Oxford, Department of Experimental Psychology, Oxford and 2 Institute of Psychiatry, London, UK
Correspondence to:
J. H. Mellanby, University of Oxford, Department of Experimental Psychology, South Parks Road, Oxford OX1 3UD, UK
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Abstract |
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There is a long-standing controversy as to whether Ammon's horn sclerosis is the result or the cause of severe limbic epilepsy. In the tetanus toxin model of limbic epilepsy, rats have intermittent spontaneous fits over a period of 3–6 weeks after injection of tetanus toxin into the hippocampus. The fits then usually remit and the EEG returns to normal. In a few rats, however, the fits recur some weeks to months later, and it was previously found that in these rats there was gross cell loss in area CA1 of the dorsal hippocampus (distant from the injection site in ventral hippocampus). Such cell loss might either promote recurrence of fits or be the result of the recurrence. In the present experiment, the effect of previous induction of CA1 cell loss by transient 4-vessel occlusion cerebral ischaemia on the subsequent development of the tetanus toxin-induced epilepsy was studied, using continuous time-lapse video monitoring to assess the number of fits. The hypothesis that the previous forebrain ischaemia would predispose rats to reoccurring fits was not supported: no rats in the ischaemia group had reoccurring fits and additionally fits were delayed and fewer occurred than in the control groups.
epilepsy; tetanus toxin; cerebral ischaemia; CA1
ANOVA = analysis of variance; 4-VO = 4-vessel occlusion
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Introduction |
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Intractable temporal lobe epilepsy is frequently associated with Ammon's horn sclerosis, characterized by extensive loss of principal neurons in CA1, CA3 and CA4 regions of the hippocampus, with relative sparing of CA2 and the dentate gyrus (see Margerison and Corsellis, 1966
; Bruton 1988; Honavar and Meldrum, 1997). Experimental studies (Meldrum, 1997) support the concept that the cell loss is the result of complex febrile convulsions or other prolonged seizures early in life (Cavanagh and Meyer, 1956; Falconer, 1974). It has been frequently suggested that this cell loss is indirectly a cause of the later occurrence of recurrent limbic seizures (Meldrum, 1997).
We have investigated this problem using the tetanus toxin model of temporal lobe epilepsy (Mellanby et al., 1977, 1984). In this model, a minute amount of tetanus toxin, a potent blocker of inhibitory transmitter release, is injected into the hippocampus of the rat. Within a few days, the rats start to have intermittent, spontaneous, limbic fits and show a variety of abnormal behaviours. This continues for several weeks; subsequently the fits wane and the EEG apparently returns to normal (Hawkins and Mellanby, 1987). There are, however, long-term sequelae to the rats having had epilepsy: there is a reduction in both excitation and inhibition in the hippocampus (Brace et al., 1985; Mellanby and Sundstrom, 1989; Jefferys and Williams, 1987; Empson and Jefferys, 1993; Jefferys and Whittington, 1996), the rats are poor at learning `hippocampal' tasks (George and Mellanby, 1982; Mellanby et al., 1982) and their social behaviour is apathetic (Mellanby et al., 1985).
In a small minority of the tetanus toxin-injected rats the fits either do not remit or recur. In one experiment with 24 rats, four had recurring seizures and showed massive cell loss in area CA1. This prompted the suggestion (Mellanby, 1993) that such cell loss was a predisposing factor for recurrence of fits. It did not appear to be a sufficient condition for recurrence, since in this experiment there was also a rat with such cell loss which did not apparently have recurrent fits. In the present work, the possibility that major cell loss in CA1 predisposes to recurrence of fits has been investigated by first inducing such cell loss by transient cerebral ischaemia [15 min of carotid artery occlusion in the 4-vessel occlusion (4-VO) model (Pulsinelli and Brierley, 1979; Pulsinelli et al., 1982)] and then comparing the epileptic syndrome induced by intrahippocampal injection of tetanus toxin in these rats with that in similarly toxin-injected sham-operated controls (and toxin-injected non-operated controls). Before being injected with tetanus toxin, the rats were tested on a task which is known to be sensitive to hippocampal damage (delayed alternation in a T-maze) to confirm that the 4-VO had produced significant damage.
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Material and methods |
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Animals
Thirty, male Sprague Dawley rats (Harlan UK Ltd, Bicester, UK) weighing 250–280 g at the start of the experiment were used. They were kept on a 12 h light/dark cycle (07.00 to 19.00 hours) and were caged in pairs with food and water ad libitum. There were three groups of 10 rats: those with 4-vessel ischaemia (4-VO group), a sham-ischaemia group and a control unoperated group.
4-VO
This was a 2-day procedure (Pulsinelli and Brierley, 1979; Lekieffre and Meldrum, 1993). On the first day the rat was anaesthetized with halothane and both vertebral arteries were electrocoagulated. The common carotid arteries were then exposed and suture threads were inserted round them and brought to the surface. On the second day the ischaemia was induced by pulling the ties tight. This abruptly reduces cerebral blood flow by 95% and the righting reflex is lost within 1–2 min.
For this experiment a 15 min period of ischaemia was used. In the sham-operated rats the vertebral arteries were electrocoagulated but the common carotid arteries were not occluded. The animals were monitored daily for a week after the operation to check for any neurological deficits as a result of the surgery/ischaemia.
Delayed alternation in a T-maze
This test was adapted from that of Wikmark and colleagues (Wikmark et al., 1973). The rats were gradually accustomed to food deprivation so that they could obtain their nutritional requirements in a period of 1 h per day. The T-maze had a grey start arm and one black and one white choice arm. On two consecutive days the animals were familiarized with the maze and the food rewards (frosted cornflakes). On the first 3 days of training two trials per rat were carried out, from then on 17 trials per day. On the first trial, both arms were baited. The rat was put into the start arm, facing away from the choice area. Once the rat had made its choice, the door to that arm was closed, the side it chose was noted and it was allowed to eat the reward. The rat was then removed from the maze and put into a separate `waiting box' for 10 s and then returned to the maze as before. The arm opposite that which the animal had chosen on the previous trial was now the only one that was baited. If the animal alternated it was again allowed to eat the reward and then put into the waiting box for 10 s until the next trial, when the opposite arm was baited. If it had made the incorrect choice (i.e. not alternated) it was allowed to find out that there was no reward and was then removed to the waiting box and 10 s later it was returned to the maze, when the bait would have been changed to the other side. The training sessions were carried out daily for each rat until it attained a criterion of six or fewer errors (trials on which it did not alternate) on 3 consecutive days.
Injection of tetanus toxin
The tetanus toxin (Wellcome Biotech, now Glaxo-Wellcome, Beckenham, UK) was dissolved in phosphate gelatin buffer (0.1 M phosphate buffer at a pH of 7.0, with 0.2% w/v gelatin) and stored at –7°C. The toxin was assayed using the method of Mellanby and colleagues (Mellanby et al., 1968).
Anaesthesia and surgical procedure
The rats were anaesthetized with an intraperitoneal injection of Equithesin at a dose of 3 ml/kg [sodium pentobarbitone (Sagatal, May and Baker Ltd, Dagenham, UK), 60 mg in 1 ml water] 81 ml; propylene glycol 198 ml; ethanol 50 ml; chloral hydrate 21 g; magnesium sulphate 10.6 g; made up to 500 ml with distilled water.
Once anaesthetized they were placed in a Kopf stereotaxic frame with the incisor bar set at +0.5. The toxin was injected from a 5 µl Hamilton microsyringe mounted on the instrument with the coordinates: ap +0.34, lat +0.48, vert –0.2, (de Groot, 1967). The toxin (0.5 µl, dissolved in phosphate gelatin buffer, containing approximately 10 mouse LD50) was injected over 2 min and then the needle was left in place for a further 5 min to prevent reflux of the toxin back up the needle track.
Filming
Video equipment
After recovery, the rats were filmed continuously 24 h/day to screen for epileptic fits for the first 4 weeks after operation. Eight rats could be filmed at a time (four cages, each with two rats). They were filmed using a Link Electronics camera containing an infrared sensitive tube. This was connected to a time-lapse video recorder (Panasonic VTR NV 8030). The films were played back on a Panasonic WV5 340 monitor at 20 times the recording speed and fits scored (see Brace et al., 1985). During the day (07.00 to 19.00 hours) the rats were filmed in fluorescent light and at night an infrared light was used. Both lights were controlled by timer switches. Over the following 5 months, the rats were inspected regularly and filmed for 1 week in each 4.
Histology
Each rat was anaesthetized with an intraperitoneal injection of sodium pentobarbitone (Sagatal). The rats were transcardially perfused with 50 ml saline (0.9%) followed by 100 ml formol saline. The brains were removed from the skulls and placed in 30% sucrose in formol saline to cryoprotect them. Once the brains had `sunk' they were embedded in Tissue Tek OCT compound and frozen in super-cooled isopentane. Coronal sections of 20 µm thickness were cut through the hippocampus, on a cryostat. The sections were mounted on gelatinized slides and stained with cresyl violet.
Experimental protocol
The ischaemic (and sham) procedure was carried out at the Institute of Psychiatry. The rats were kept there for 2 weeks and then transferred to Oxford. They were then handled daily and gradually put on to a 1 h per day feeding schedule such that they obtained adequate nutrients during that time. Seven weeks after the ischaemic operation, the training on the T-maze was started. Ten weeks after the ischaemia, the tetanus toxin was injected bilaterally into the hippocampus and they were then filmed continuously for the next 4 weeks, followed by 1 week in 4 for 18 weeks. Thirty-two weeks after the ischaemia the rats were sacrificed for histology.
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Results |
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T-maze
The 4-VO group of rats performed worse on the T-maze when compared to the sham-ischaemia and unoperated control groups (Table 1
). Analysis of variance (ANOVA) revealed a statistically significant difference between groups. Post hoc t-tests showed that on both measures (days to criterion and errors on day 18) the 4-VO rats were significantly worse than either the sham or the control rats, but there were no significant differences between the sham and the unoperated rats.
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Behaviour
The rats were weighed and handled regularly. All the rats had been injected with tetanus toxin and were somewhat hyper-reactive during the weeks when they were having overt fits. There was no noticeable difference in general behaviour between the groups which had previously been made ischaemic and the two control groups. The rats tended to lose weight at around the time they started having overt fits. This did not last long and they started gaining weight again within a week. Due to the fact that the 4-VO group started fitting slightly later, this weight loss also occurred slightly later. Long term (2, 3 and 4 months after the toxin injection) there was no difference in weights, when calculated as a percentage of the original weight, between any of the groups.
Fits
The 4-VO group of rats started fitting later than the sham and control groups and they had fewer fits (Table 2) (ANOVA, significant differences between groups on all three measures). Post hoc t-tests showed that the 4-VO group was significantly different from each of the control groups, and there were no significant differences between the sham and control groups. The different time-courses of the syndrome in these three groups of rats are illustrated in Fig 1.
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There was no evidence of reoccurring fits in any of the 4-VO rats. One of the rats in the control (toxin only) group was seen to have reoccurring fits 4 months after toxin injection.
Histology
All the rats in the 4-VO group had a bilateral lesion in the CA1 region and this was found predominantly in the dorsal CA1, although the extent of the lesion did vary slightly from rat to rat (Fig. 2). It was restricted to CA1 and did not appear to affect any of the other cell layers in the hippocampus.
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One rat in the sham-ischaemia group and the rat in the unoperated (toxin-injected) control group that had reoccurring fits, had CA1 cell death. No other rats in this group had CA1 cell death.
The appearance and extent of the CA1 lesion was broadly similar to the sporadic lesion seen after tetanus toxin injection alone (Fig. 3).
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Discussion |
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The 4-vessel ischaemia consistently caused loss of pyramidal neurons in CA1. While it is probable that this loss was mainly responsible for the effects on both the animals' ability to perform the delayed alternation task in the T-maze and the development of epilepsy, we cannot exclude a contribution from other forebrain areas showing a lower degree of ischaemic vulnerability. However, reversal of the spatial learning deficit shown in the Morris water maze following 15 min of 4-vessel occlusion is seen with CA1 but not CA3 cell grafts (Netto et al., 1993
; Hodges et al., 1996). Interestingly, the T-maze learning deficit observed here is less pronounced than that seen previously in rats which had recovered from tetanus toxin-induced epilepsy (Mellanby et al., 1982). The finding that there was no difference in performance between the sham and control groups indicates that the sham procedure, as expected, had not produced functional damage as measured by performance on this task. The original hypothesis that CA1 cell death would predispose rats to reoccurring fits is not supported by our results. On the contrary, the fits were delayed, fewer occurred than in the control groups and no rats in the 4-VO group had reoccurring fits.
Jefferys (Jefferys, 1989) has demonstrated that hippocampal slices prepared from rats with the tetanus toxin-induced syndrome generate short bursts of spontaneous seizure activity which originate in the CA3b/c region. The long seizure discharges (i.e. >20 s) which seem to be needed for the production of generalized seizures in the intact animal are only recorded in vivo (Hawkins, 1985; Hawkins and Mellanby, 1987; Finnerty, 1993). Finnerty (Finnerty, 1993) has argued that such generalization requires what he has called a `distributed focus', i.e. seizure activity arising both within an injected hippocampus and through its connections round the limbic system via a mirror focus in the opposite hippocampus. In the intact brain there are thus multiple pathways through which seizure activity in the hippocampus can circulate. Bilateral destruction (by 4-VO) of the CA1 cell layer would interrupt some of the circuitry on which generalization of seizure activity presumably depends: in particular, within the toxin-injected hippocampus, the circuit from CA3 back to entorhinal cortex (direct or via the subiculum) and the link across the commissures from CA3 to the opposite CA1. The slower development of generalized seizures and the lesser intensity of the syndrome in the bilateral absence of CA1 (after 4-VO ischaemia) supports the hypothesis of Finnerty (Finnerty, 1993) that it is the simultaneous contribution of distributed cell arrays that leads to the development of recurrent fits.
Do the present experiments in any way `clarify the relationship between this altered morphology and both the cause and the result of seizure disorder' (Armstrong, 1993)? In the tetanus toxin model of hippocampal epilepsy it appears that where CA1 cell loss occurs it usually takes place within the first 7 days after toxin injection, and hence is likely to be caused by early seizure activity rather than by recurrence of seizures. Such a conclusion fits with the widely held belief with respect to temporal lobe epilepsy that febrile seizures in infancy are frequently responsible for Ammon's horn sclerosis which then increases the likelihood of developing limbic seizures (Cavanagh and Meyer, 1956; Sagar and Oxbury, 1987). Thus, Ammon's horn sclerosis is found in 47–70% (depending on the hospital) of surgically resected hippocampi (removed as treatment for drug-refractory temporal lobe epilepsy) and 75% of these patients had complex febrile or prolonged seizures in infancy or early childhood (see Armstrong, 1993; Meldrum, 1997; Honavar and Meldrum, 1997).
Why are limbic seizures particularly likely to occur in the remaining neuronal circuitry after the development of Ammon's horn sclerosis? It is unlikely that it is a direct consequence of CA1 cell loss, first because the cell loss is immediate following the prolonged seizure in early life, but the seizures appear many years later in childhood or adolescence, and secondly we show that such a lesion does not facilitate epileptogenesis in a rodent model of limbic epilepsy. Nevertheless, temporal lobe seizures in man may be an indirect result of hippocampal cell loss, interacting with developmental or regenerative processes. One candidate for this has been the sprouting of mossy fibres within the dentate gyrus molecular layers. The recurrent excitatory synapses (Frotscher and Zimmer, 1983) on the granule cells of the dentate gyrus which normally gates the entry of seizure activity into the hippocampus might now promote its entry. Such sprouting was originally shown in kindled rats (Sutula et al., 1988) and has been shown in the tetanus toxin model (Mitchell et al., 1996), in rats treated with kainic acid (e.g. Nadler et al., 1980; Tauck and Nadler, 1985; Cronin and Dudek, 1988; Mathern et al., 1990; Sloviter, 1990, 1992; Chakravarty et al., 1997), and has also been demonstrated in resected brain tissue from cases of human epilepsy (Babb et al., 1988, 1991; Houser et al., 1990; Mathern et al., 1996).
We have recently investigated a toxin-injected rat which had recurrent seizures but in which we found that the CA1 cell layer was intact (Milward, 1997). From this it can be concluded that cell loss in CA1 is neither necessary nor sufficient to cause recurrence of seizures. Indeed, the current experiments suggest that on its own, CA1 cell loss is more likely to restrict rather than promote development of generalized seizures. Finally, it is of general interest that 15 min of 4-VO was not a sufficient insult either to cause or to promote the production of seizures.
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Acknowledgments |
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We wish to thank Mr P. Sowinski for his expert technical assistance. A.J.M. held an MRC studentship.
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Received August 7, 1998. Revised November 16, 1998. Second revision on January 15, 1999. Accepted January 18, 1999.
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