119

Behavioural Brain Research, 40 (1990) 119-129 Elsevier BBR 01100

Radial maze performance following hippocampal kindling L. Stan Leung 1, Kathy A. Boon 1, Taro Kaibara 1 and Nancy K. Innis 2 Departments of JClinical Neurological Sciences, Physiology and 2Psychology, University of Western Ontario, London, Ont. (Canada) (Received 22 February 1990) (Revised version received 18 June 1990) (Accepted 18 June 1990)

Key words: 8-Arm-maze; Kindling; Working memory; Interictal spike; Seizure

The relation between hippocampal epileptiform activity and 8-arm radial maze performance was assessed following repetitive afterdischarges (ADs) evoked by stimulation of the hippocampal CA1 region (kindling). Hippocampal kindling, whether to stage V (generalized) convulsions or to a preconvulsive stage, induced deficits in radial maze performance, evaluated by correct arm entries in 8 choices or total maze run (trial) time. The deficits persisted at least until 21 days after the last AD. Hippocampal interictal spikes (ISs) were induced by kindling, but the rate of ISs declined to near zero in a few days. The rate or presence of ISs was not related to maze performance.

INTRODUCTION

The relation between hippocampal epileptiform activity and behavioral function has been studied in several paradigms. An electrically induced afterdischarge (AD) in the hippocampus is known to induce amnesia for a recently learned passiveavoidance task 9'22, disrupt working memory in rats on an 8-arm radial maze zS, and disrupt recent recognition memory in patients 3. The above literature does not address the question of function in an abnormal brain that has undergone repeated seizures. In the kindling model of epilepsy, where spaced, repeated ADs in the hippocampus produced progressive clinical signs of seizures, Lopes de Silva et al. 16 concluded that repeated ADs induced working (short-term) and reference (long-term) memory deficits on the 8-arm radial maze, but only reference and not working memory deficits persisted after daily kindling was stopped.

In earlier studies of hippocampal kindling, we reported that hippocampal spontaneous interictal spikes (ISs) developed during the course of kindling and declined with a time constant of 1.5 days when daily kindling was interrupted ~4. Since ISs are abnormal epileptiform transients, we hypothesize that they may interfere with hippocampal function. We chose the 8-arm radial maze to test hippocampal function, since Olton et al. 24 showed that performance on this task is sensitive to lesions in the hippocampus or closely related structures. In order to study the effects of seizure (AD) and/or ISs on hippocampal function, we adopted the following testing procedure. (1) Rats were trained before kindling but were not run on the maze until kindling was completed, in order to minimize interference of kindling with training. (2) Rats were tested on the maze at times of both high and low interictal spike rates. Part of the study has been reported in an abstract ~5.

Correspondence: L.S. Leung, Department of Clinical Neurological Sciences, University of Western Ontario, University Hospital, 10th floor, London, Ontario N6A 5A5, Canada. 0166-4328/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)

12(I MATERIALS A N D M E T H O D S

Experiment I. Fully kindled rats

Subjects Twenty-two male hooded rats of a LongEvans strain, about 15-20 weeks old and weighing 300-400 g during surgery, were used as subjects. After surgery, all animals were housed individually in standard rat cages and were maintained on a 12-12 h light/dark cycle. Ten days after surgery, they were reduced to 85 ~o of ad libitum weights by limiting access to food.

Surgical and recording methods Under pentobarbital anesthesia (60mg/kg i.p.), bipolar 125-#m wire electrodes were implanted into both the left and right hippocampus (3.5 mm posterior and 2.7 mm lateral to bregrna on a flat skull, 3.1 mm deep for the deep electrode; for details, see ref. 11). On each side, the deep electrode of the bipolar pair was targeted at the CA 1 stratum radiatum, and the surface one was placed at near the alveus. At least 10 days after surgery, EEGs from the 4 hippocampal electrodes (referred monopolarly to a frontal screw) were recorded on a polygraph (Grass 7D) machine 13. Only rats with > 0.5 mV hippocampal theta rhythm at the deep electrode were used for the behavioral study below. After the completion of the experiment, all rats were euthanized by an overdose of pentobarbital and perfused with saline followed by 4,°/o formaldehyde. Coronal sections of the brain were made and stained with thionin or gallocyanin.

Apparatus and procedure Maze-trainingphase. The animals were studied on an elevated, open radial maze, consisting of a central platform from which 8, equally spaced arms radiated like the spokes of a wheel. The hexagonal central platform was 51 cm in diameter and the arms were 21 × 10 cm with small food cups at the ends of the arms. The maze stood 85 cm above the floor, in a fixed location at the corner of a room; it was surrounded by a wall, a window, a black and a white curtain. The observer always sat in the same location at one side of the maze.

Preliminary training consisted of handling the rats and then placing them as a group in an open field, following which they were placed individually on the central platform of the maze, with food pellets scattered over the floor of the entire maze. Food was gradually placed only on the arms and then at the ends of the arms. After about 6 days on the maze the rats were consistently running to the ends of the arms. During maze training, each arm was baited with two 45-mg Noyes pellets and the rat placed on the central platform. It was allowed to visit the arms until all the food had been collected or 10rain had elapsed. An observer recorded the sequence of arm visits and the time it took to collect all the food. An error was recorded when an animal re-entered a visited arm. Training consisted of one daily trial 5 days/week between 9.00 and 14.00 h. The animals were trained on the maze until they met a performance criterion of a moving average of < 1 error per trial over 5 consecutive trials. Training was followed by a period of overtraining consisting of at least 12 days (range 12-21) of criterion performance. At this point pairs of rats were matched on their rate of maze acquisition, and randomly assigned as either control or experimental animal. Kindling phase. The experimental rat from each pair received hourly stimulation of the hippocampus, up to 8 times a day. At the same time, the control rat was handled but not stimulated A 1-s train of 200 Hz, 50-300ttA intensity, 0.5 ms pulse duration was used to elicit an AD in the hippocampus. Intensity used was within 50/~A of the AD threshold as determined by approximation at the beginning of kindling ~2. ADs from hippocampal electrodes were recorded on polygraph paper and spontaneous E E G during waking immobility and food chewing was recorded immediately before an AD. The kindled rat and its control were not run on the maze until kindling completion, defined as the achievement of 5 - 6 stage V seizures (bilateral clonus with rearing and falling26). No more than two stage V seizures were evoked on the last day of kindling. Postkindling phase. Postkindling testing was divided into 3 periods. The first period (postkindling I) began the day following the completion of kindling and was designed mainly to assess

121 the relation between ISs and maze performance. Rats were tested on the maze on day 1 (22-24 h after the last AD) and day 4 after the last AD. Following the day 4 trial, 5 hourly stimulation trains each evoking an AD were then delivered to the experimental rats, and maze performance was assessed on the first (day 1' and fourth (day 4') days after rekindling. At least 3 min of artifact-free EEG during food-chewing was recorded on each day after the maze run. Following d a y 4 ' , the rats remained in their home cages for 15-18 days rest, after which they received 7 consecutive dally trials on the maze (postkindling II). EEG during food-chewing was recorded on at least 1 day during this period, typically the last day. The third period of testing (postkindling III), which followed immediately, also consisted of 7 consecutive dally trials on the maze, each preceded 2 2 - 2 4 h by an AD (delivered shortly after the trial on the preceding day). Recordings. ISs were visually discriminated in the hippocampal EEG recorded during foodchewing, usually with the aid of a window discriminator. A wide-band (0.5 Hz to 3 kHz) hippocampal signal was high-pass filtered (3 dB at 150Hz) and amplitude-discriminated by a window discriminator. Standard pulses from the discriminator indicated a sharp slope. An IS was operationally defined as having both a sharp slope and > 1.5 times background amplitude. Settings of the window discriminator and the criteria for ISs remained the same for individual rats across different days. ISs were scored blindly, without explicit knowledge of the day of recording. Three measures of maze performance were examined. (1)A choice score - - the number of correct arm entries in the first 8 choices; (2) the total number of errors (re-entries) per trial; and (3) the time to complete a trial (obtain all 8 food pellets; 10 min maximum). Two factor (trial and group) analyses of variance (ANOVA) compared maze performance in the following periods:. (1)acquisition (the last 10trials before achieving criterion); (2)overtraining (the last 10 trials before kindling/lay off; (3) postkindling I (days 1, 4, 1', 4' as defined above); (4) postkindling II (7 trials after a rest of

15-18 days); and (5) postkindling III (7 trials, each preceded by an AD on the previous day).

Experiment H. Partially kindled rats Another group of 16 male hooded rats was used to evaluate the effects of partial kindling. The procedures for housing, testing and recording were the same as in Expt. I except that the kindled rats only received a maximum of 35 ADs or one generalized seizure, whichever came first. The acquisition and overtraining procedures were the same as Expt. I. Postkindling testing consisted of only two periods. Postkindling I was identical to Expt. I, and postkindling II consisted of 8 consecutive daily trials after 17-24 days rest from day 4'. RESULTS

Experiment I. Fully kindled rats Kindling and AD progression Histological sections revealed that the deep electrodes in all kindled and control rats were in the hippocampus. In particular, for 7 of the 8 kindled rats which completed the behavioral experiment, the deep stimulating electrode (cathode) was located at CA1 stratum radiatum (n = 3), CA1 alveus (n = 2), CA3 alveus (n = 1) and molecular layer of the dentate gyrus (dorsal blade, n = 1). Histology from one pair of kindled/control rats was not available but physiological recording indicated that the deep electrodes were within the hippocampus since a highamplitude ( > 0.5 mV) theta rhythm was found. The initial AD threshold was 147 + 2 2 # A (mean + S.E.M., n = 9). The typical AD of each rat consisted of a primary AD followed by a secondary AD discharge, typical of that evoked by stimulation of the hippocampal CA 1 region ~2. The hourly kindled rats in this study reached their first and fifth stage V seizure with 57.9 + 10.9 and 72.7 + 10.4 ADs, respectively. This can be compared with 40.3 _+ 6.0 and 46.3 + 6.0 ADs (n -- 7) for reaching the first and fifth stage 5 seizure in rats kindled dally with similar hippocampal electrode sites '2. However, the mean number of ADs

122 to reach one (or 5) stage V seizure is not significantly (Mann-Whitney U-test P > 0.05) larger in hourly than daily kindling. The only significant difference between the groups P < 0.002, Mann-Whitney U-test) is the number of ADs required from the first to the fifth stage V seizure. The latter number averaged 14.8 + 1.8 ADs (n = 9) for hourly kindling and 6 + 0.6 ADs (n = 7) for daily kindling. In other words, the hourly kindled rats were less consistent than daily kindled rats in having stage V seizures.

Prekindling maze performance for the experimental and control rats is shown in Fig. 1A, C. Data are from the last 10 sessions before criterion was achieved and the last 10 sessions of overtraining. There were no differences between the two groups on the choice score measure (number of correct arm entries in the first 8 choices) during acquisition or overtraining (Fig. 1A and Table I), as would be expected since rats were matched on this variable for group assignment. Although the experimental rats initially took longer to complete a trial, this difference had disappeared by the end of overtraining (Fig. 1C and Table 1). During overtraining, a rat would often adopt an adjacent arm response pattern 4, i.e. circle in one fixed direction and visit each arm in sequence (Table II). On other trials, a non-adjacent arm response strategy (NAA) was used. During the period in which the experimental animals were being kindled, neither animal in a pair was exposed to the maze. The kindling proce-

Maze performance Eight pairs (16 of 22) rats completed the experiment. Four rats were excluded from the kindling phase because they could not maintain criterion performance. One pair was discarded because of recurring feeding problems in the experimental rat before and during the kindling phase; this rat was fully kindled and subsequently refused to enter any maze arms after day 1'

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TABLE III

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For each kindled rat, the rate of ISs declined after kindling cessation (day 1 to day 4), increased with rekindling ( d a y 4 to day 1'), and then declined from day 1' to day 4' (Fig. 2). The exact rate of IS decline varied somewhat among rats but the average IS rate decayed with a time constant of 1.66days (day 1 to day4, Fig. 2A). The average IS rate during food-chewing on postkindling day 1 was 28.2 + 7.6 spikes/rain (n - 8). There were almost no detectable ISs for control rats on any day or for experimental rats at > 14 days after kindling. There appears to be no relation between the mean IS rate and mean maze errors in the kindled rats (Fig. 2A). Maze errors remained relatively stable while IS rate fluctuated greatly between postkindling day 1 to 4, day 4 to 1' and day 1' to 4'. Similarly in individual rats, there is no significant correlation between maze errors and IS rate, whether transformed linearly or logarithmically.

Experiment H. Partially kindled rats These experimental rats were kindled to 35 ADs (n = 6) or one AD after the first stage IV seizure (bilateral forelimb clonus with rearing; n = 2). The kindled/lay-off period was 11.8 + 0.9 days. Two kindled rats lost their head caps during or before re-kindling, and their data (and the data of their paired controls) were discarded from further analysis of variance. Six kindled rats and their controls completed the behavioral tests. Five rats had 35 ADs and the sixth 33 ADs, with one stage IV seizure on the 32nd AD. The effect of kindling on maze performance in the partially kindled rats (Fig. 4) was similar to that of the fully kindled rats (Fig. 1). Choice performance and trial times on the maze were not different between control and experimental rats for the acquisition and overtraining periods. Both measures were significantly dif-

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ferent for the groups during the two postkindling periods, except that choice performance tended to show an improvement during postkindling period II, such that there was no significant difference between kindled and control rats for the last 4 days of testing. There is no effect of repeated trials for either of the two measures during any period except acquisition. No interaction (trial x group) effect was found. The probability of using a NAA strategy was 0.39 + 0.15 and 0.45 + 0.14 before and after the lay-off period for the control rats (n = 8). The same probability measure for kindled rats (n = 8; two rats which lost their headcaps were included) was 0.29 + 0.13 and 0.94 + 0.05 before and after kindling. The probability of using a NAA strategy increased after kindling for every kindled rat. In contrast to Expt. I, there was no significant change in response strategy for the control rats following lay-off. The rates o f l S in the partially kindled rats were generally lower than in fully kindled rats on the same day after kindling. The average spike rate was 7.6 + 3.5/min on postkindling day 1. The

general decline of I S across days remained similar to that observed in Expt. I. Similarly, there was no correlation between IS rate and maze performance individually or as a group (Fig. 2B). DISCUSSION

Repeated ADs and generalized seizures induced by hippocampal kindling disrupted radial maze performance for a minimum of 3 weeks after the last AD, until the middle of postkindling II period. The disruption was primarily caused by hippocampal ADs and was not necessarily associated with behavioral convulsions. To our knowledge, we are the first to report a prolonged period of radial maze deficit after repeated hippocampal ADs. Long-term disruption of conditioned emotional response by amygdala kindling has been reported 19. The results here are consistent with those of Lopes da Silva et al.'s report 16, which found both reference and working memory deficits during hippocampal kindling. In the 7 days postkindling, Lopes da Silva et al. found reference memory

127 deficits but no working memory deficits. In contrast, we found working memory deficits to last at least 3 weeks after kindling. Our study differed from theirs in several ways. Lopes da Silva et al. used on 8-arm maze with only 5 baited arms, and trained and kindled the rat each day, while we only tested them after kindling and then after a rest period. Kindling is more likely to interfere with training in Lopes da Silva et al.'s procedure. Uninterrupted daily training may also hasten recovery of maze performance. An investigation of the running strategy used by the fully-kindled and control rats in Expt. I found that both groups abandoned the favored adjacent arm strategy after experimental manipulation (mean 20.8 days kindling/lay-off). However, after a shorter lay-off(mean 11.8 days) in Expt. II, the control rats maintained the preferred adjacentarm strategy, while the experimental rats abandoned it. Whether evaluated for trials using the NAA strategy or for all trials, the mean maze error was larger in kindled than control rats after kindling/lay-off. Thus, the deficit in spatiaF 3 or working memory24 does not depend solely on response strategy2. Choice performance and maze run times were very similar for control and experimental rats before the kindling phase, with the exception of run times during early acquisition in Expt. I. Late in acquisition and in overtraining, the rats did not differ in any performance measures used. Following kindling, choice performance decreased and run time increased in the kindled rats. Choice performance recovered to control levels during postkindlinglII in fully kindled rats. The improvement in choice performance in postkindling III was not likely caused by the AD 22-24 h preceding the maze trial, since there was already a trend of improvement during the postkindling lI period. Furthermore, performance was not worse on trials after a weekend (3 days after the last AD; not shown here) during postkindling III. This recovery of function despite continuing daily ADs may relate to the repeated daily (over)training and perhaps to the low AD frequency (daily instead of 5/day). Two main interpretations of the prolonged deficits following kindling may be made:

(1)kindling causes retrograde amnesia; and (2) kindling causes anterograde changes in the brain. To be consistent with the first interpretation, the temporal gradient of the retrograde amnesia has to extend for a period of many days since in this study the rats were overtrained for a duration of more than 2 weeks. Most literature indicates that the duration of retrograde amnesia resulting from intracranial brain (or hippocampal) stimulations is less than 24h 9"1°'22. However, more recently, Squire and Spanis 27 found retrograde amnesia induced by transcorneally electroconvulsive shocks (ECS) to last 14-21 days in mice performing a passive avoidance task. The ECS in their study was obviously more severe than the hippocampal ADs here. All the mice had clonic-tonic seizure with each ECS and 15~o of them diedZT; no rats have died during hippocampal kindling in our laboratory. In a place navigation task (watermaze), Sutherland etal. 29 found retrograde amnesic effects if multiple colchicine lesions were made in the hippocampus within 12 weeks of preoperative training. The different procedures in the two studies (kindling here us extensive hippocampal lesion) and tasks (a reference vs working memory task) preclude a meaningful comparison. While the extant literature does not lend strong support to the hypothesis of long-lasting retrograde amnesia in this study, this hypothesis should be re-evaluated in the future when relevant information is available. Anterograde physiological or morphological changes of the hippocampus and related structures may result from kindling. It has been mentioned 7 that the effects of kindling on radial maze performance resembled somewhat the effects of selective neurotoxic lesion of CA3 (kainic acid) 5, dentate gyrus (colchicine)8, or the whole hippocampus (ibotenic acid) 6 on reference memory. The change could be in the hippocampus (CA1) or related structures inside or outside of the hippocampus since repeated hippocampal ADs are known to spread to many related structures such as the entorhinal cortex and amygdala 12 and to cause whole-brain changes in various neurotransmitters (cf. ref. 20). Quantitative cell counts revealed that there is a 17.8~o decrease in cells in the hilus of the dentate gyrus

128 following 3 stage V seizures elicited from amygdala stimulations 1, accompanied by sprouting of mossy fibers in the dentate gyrus 28. We did not observe any gross loss ofhippocampal neurons, but quantitative cell count data were not obtained from our histological sections. Physiological changes in the hippocampus following local kindling include changes in synaptic responses and action potential generation, possible interpreted as long-term potentiation (LTP) 17, and long-term depression (LTD) 18"3°, and the induction of ISs '3. McNaughton et al. 21 reported that LTP of the perforant path to dentate synapse did not affect working memory. Whether LTP or LTD in CA1, induced with or without an AD, affects working memory is not known. However, we have demonstrated that the decline in IS rate was not accompanied by a significant improvement in maze performance. We conclude that the rate of IS (recorded during food-chewing) does not predict maze performance. On the other hand, since ISs occurred only during behaviors accompanied by an irregular hippocampal EEG (e.g. immobility, slow-wave sleep, grooming, food-chewing) and not during actual running of the maze (which is accompanied by a hippocampal theta rhythm), it may be argued that IS is an irrelevant measure. Perhaps behavioral activation of cholinergic and other inputs, which remain relatively intact after kindling ~3, is one means by which the brain can act to suppress irrelevant 'noise' such as ISs, and thus maintain relatively normal brain function. ACKNOWLEDGEMENTS

We thank Adam Blackman and Dwight Stewart for technical assistance during the early phase of the experiment, and Bev Hughes for typing the manuscript. The research was supported by NIH R01-NS25383. REFERENCES 1 Cavazos, J.E. and Sutula, T.P., Progressive neuronal loss induced by kindling: a possible mechanism for mossy fiber synaptic reorganization and hippocampal sclerosis, Epilepsia, 30 (1989) 702. 2 Dale, R.H.I. and Innis, N.K., Interactions between

response stereotypy and memory strategies on the eightarm radial maze, Behav. Brain Res., 19 (1986) 17-25. 3 Halgren, E. and Wilson, C.L., Recall deficits produced by afterdischarges in the human hippocampal formation and amygdala, Electroencephalogr. Clin. Neurophvsiol., 61 (1985) 375-380. 4 Innis, N.K. and Macgillivray, M., Radial maze performance under food and water deprivation, Behav. Proc., 15 (1987) 167-179. 5 Jarrard, L.E., Selective hippocampal lesions and behavior: effects of kainic acid lesions on performance of place and cue tasks, Behav. Neurosc., 97 (1983) 873-889. 6 Jarrard, L.E., Selective hippocampal lesions and behavior: implications for current research and theorizing. In R.L. Isaacson and K.H. Pribram (Eds.), The Hippocampus, Vol. 4, 1986, pp. 93-126. 7 Jarrard, L.E. and Walczak, D.D., Effects of hippocampal kindling on performance of a complex place and cue memory task in the rat, Soc. Neurosci. Abstr., 12 (1986) 743. 8 Jarrard, L.E., Okaichi, H., Goldsehmidt, R. and Stewart, O., On the role of the hippocampal connections in the performance of place and cue tasks: comparisons with damage to hippocampus, Behav. Neurosci., 98 (1984) 946-954. 9 Kesner, R.P. and Doty, R.W., Amnesia produced in cats by local seizure activity initiated from the amygdala, Exp. Neurol., 21 (1968) 58-68. 10 Kesner, R.P. and Wilburn, M.W., A review of electrical stimulation of the brain in context of learning and retention, Behav. Biol., 10 (1974) 259-293. 11 Leung, L.S., Behavior-dependent evoked potentials in the hippocampal CA1 region of the rat. I. Correlation with behavior and EEG, Brain Res., 198 (1980) 95-117. 12 Leung, L.S., Hippocampal electrical activity following local tetanization. I. Afterdischarges, Brain Res., 419 (1987) 173-187. 13 Leung, L.S., Hippocampal interictal spikes induced by kindling: relations to behavior and EEG, Behav. Brain Res., 31 (1988) 75-84. 14 Leung, L.S., Spontaneous hippocampal interictal spikes following local kindling: time-course of change and relation to behavioral seizures, Brain Res., in press. 15 Leung, L.S., Boon, K.A., Innis, N.K. and Blackman, A., Relation between radial maze performance and hippocampal interictal spikes following hippocampal kindling, Epilepsia, 30 (1989) 702. 16 Lopes de Silva, F.H., Gorter, J.A. and Wadman, W.J., Kindling of the hippocampus induces spatial memory deficits in the rat, Neurosci. Lett., 63 (1986) 115-120. 17 Maru, E. and Goddard, G.V., Alternation in dentate neuronal activities associated with perforant path kindling. I. Long-term potentiation of excitatory synaptic transmission, Exp. Neurol., 96 (1987) 19-32. 18 Maru, E. and Goddard, G.V., Alternation in dentate neuronal activities associated with perforant path kindling. III. Enhancement of synaptic inhibition, Exp. Neurol., 96 (1987) 46-60.

129 19 McIntyre, D.C. and Molino, A., Amygdala lesions and CER learning: long-term effect of kindling, Physiol. Behav., 7 (1972) 1055-1058. 20 McNamara, J.O., Bonhaus, D.W., Shin, C., Crain, B.J., Gellman, R.L. and Giacchino, J.L., The kindling model of epilepsy: a critical review, CRC CriticalReview Neurobiol., 1 (1985) 341-391. 21 McNaughtom B.L., Barnes, C.A., Rao, G., Baldwin, J. and Rasmussen, M., Long-term enhancement of hippocampal synaptic transmission and the acquisition of spatial information, J. Neurosci., 6 (1986) 563-571. 22 McDonough, Jr. J.H. and Kesner, R.P., Amnesia produced by brief electrical stimulations of the amygdala or dorsal hippocampus in cats,J. Comp. Physiol. Psychol., 77 (1971) 171-178. 23 O'Keefe, J. and Nadel, L., Hippocampus as a Cognitive Map, Oxford University Press, London, 1978. 24 Olton, D.S., Becker, J.T. and Handelman, G.E., Hippocampus, space, and memory, Behav. Brain Sci., 2 (1979) 313-322. 25 Olton, D.S. and Wolf, W.A., Hippocampal seizures pro-

duce retrograde amnesia without a temporal gradient when they reset working memory, Behav. Neural Biol., 33 (1981) 437-452. 26 Racine, R., Modification of seizure activity by electrical stimulation: II. Motor seizure, Electroencephalogr. Clin. Neurophysiol., 32 (1972) 281-294. 27 Squire, L.R. and Spanis, C.W., Long gradient of retrograde amnesia in mice: continuity with the findings in humans, Behav. Neurosci., 98 (1984) 345-348. 28 Sutula, T., He, Xiao-xian, Cavazos, J. and Scott, G., Synaptic reorganization in the hippocampus induced by abnormal functional activity, Science, 239 (1988) 1147-1150.

29 Sutherland, R.J., Arnold, K.A. and Rodriguez, A.R., Anterograde and retrograde effects on place memory after limbic or diencephalic damage, Soc. Neurosci. Abstr., 13 (1987) 1066. 30 Wadman, W.J., Leung, L.S., Lopes da Silva, F.H. and ten Veen, J., Permanent changes in AEP and the development of epileptic spikes during kindling of rat hippocampus, Neurosci. Lett., 7 (1981) $466.

Radial maze performance following hippocampal kindling.

The relation between hippocampal epileptiform activity and 8-arm radial maze performance was assessed following repetitive afterdischarges (ADs) evoke...
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