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Local cerebral glucose utilization in epileptic seizures of the mutant El mouse
359
Brain Research, 266 (1983) 35%363 Elsevier Biomedical Press
Local cerebral glucose utilization in epileptic seizures of the mutant El mouse J I R O S U Z U K I , Y U R I E N A K A M O T O and Y O S H I H I R O S H I N K A W A
Division of Neurophysiology, Psychiatric Research Institute of Tokyo 2-1-8, Setagaya-ku, Tokyo, 156 (Japan) (Accepted D e c e m b e r 28th, 1982)
Key words: epilepsy -- E 1 m.ouse -- 2-deoxyglucose - h i p p o c a m p u s - focus - neocortex - excitation - brainstem
The neural p a t h w a y a n d the focus o f the epileptic seizure o f m u t a n t E1 mice were studied by the [14C]2-deoxyglucose technique. In the mice with full t o n i ~ c l o n i c seizure, the entire neocortex and h i p p o c a m p u s showed a remarkably increased m e t a b o l ic rate. By contrast, a lower metabolic rate was evident in the thalamic nuclei, central gray, locus coeruleus and some interstitial nuclei. The epileptic focus in E 1 mice p r e s u m a b l y exists in the h i p p o c a m p u s .
Paroxysmal neural activities in the brain With epileptic seizures could be expected to be accompanied by corresponding changes in local metabolic ratO 3. We have now looked for the neural pathway and the focus involved in the seizure of E 1 mice, an inbred mutant strain susceptible to epilepsy, using the [~4C]2-deoxy-Dglucose (2-DG) method for measuring local cerebral glucose utilization. The E1 mouse is an excellent model of hereditary or idiopathic epilepsy: it was discovered in 19545, registered internationally in 19646, and established electroencephalographically as an epilepsy model in 197614. Preliminary reports of this research were presented at the Epilepsy International Symposium ~8, and other occasions 16,~7. Further quantitative details will be presented elsewhere. About 30 El mice studied were adult o f F 65 to 71, which were kept in our animal center. Radioactive samples of 2-DG (specific activity 58.5 m C i / m m o l ) were obtained from Radiochemical Center, Amersham, and preparations of 3.5 ~Ci/25 g of body weight in physiological saline were administered via the jugular vein. During 40 min after 2-DG administration, a mouse was given seizure-inducing stimulation and then sacrificed. The conditions for provoking seizure and of applying 2-DG to a mouse were reported previously~°,~L Briefly, our method for inducing seizures consists of two steps: observing the mice 0006-8993 / 83/0000- 0000/$03.00 © 1983 Elsevier Science Publishers
on the metal mesh for 3 min and then tossing them up in the air about 10 cm ~5. The radioactivity (RA) in the blood following i.v. administration was 1.%3.3% of the injected RA at 40 min after the injection. 2-DG level in the brain after i.v. administration reached the highest level (about 1.9%) within 5 min, which was maintained for 60 min and thereafter gradually decreased. The time course and the level of concentrations ( d p m / m g of tissues) of 2-DG in the brains of both E1 and D D Y mice showed similar results l°. Based on these facts, all the E1 and control mice used were executed 40 min after the administration of 2-DG. The frozen brain was serially sectioned at 20 #m, mainly in a frontal or horizontal plane. These sections and a set of [~4C]methyl methacrylate standards (Amersham) were placed on X-ray film for a 2 week exposure period. For the location of a nucleus, positive identification was made with the aid of an adjacent histological section stained with cresyl violet, and was referred to the atlas by Sidman et al. 12 In the normal freely moving state, there was no significant difference between autoradiographs of an E1 mouse and a control D D Y mouse. In the E1 mice which exhibited full tonic-clonic seizures twice or three times during 40 min after 2-DG administration, the findings were re-
360 whole hippocampus and associated areas (Fig. 1B2,3). The pyriform cortex, entorhinal cortex and amygdala partially showed a higher density in the seizure mouse (Fig. 1B~_3). By contrast, various parts of the brain which had a higher meta-
markable. As shown in Fig. 1Bf_3, the entire neocortex of the seizure mouse demonstrated a very dense radiolabeling, namely a higher metabolic rate, compared with the normal. The most striking increase of density was observed in the
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Fig. 1. [14C]Deoxyglucose autoradiographs of coronal sections and cresyl violet-stained Nissl sections of El mouse brains. The autoradiographs of the 14C standards are also visualized. A: sections with no seizure. B: sections with 3 full seizures. C: N issl sections adjacent to the sections in B. CER, neocortex; C/P, caudate/putamen; PYR, pyriform cortex; HYP, hypothalamus; HIP, hippocampus; TH, thalamus; AMY, amygdala; ZI, zona incerta; CING, cingulate cortex; COL. A; anterior colliculus; INT. C., Cajal's interstitial nucleus; ER, entorhinal cortex; TEG, tegmentum; SN, substantia nigra; COL. P, posterior colliculus; MCG, mesencephalic central gray; CEL, cerebellum; VES, vestibular nucleus; LC, locus coeruleus.
361 compared with normal (Fig. 1B3). In an E1 mouse with full seizures it is very interesting that, in short, the mantle parts of the brain showed increased radiolabeling, while the central parts showed decreased radiolabeling. Another interesting feature of an E1 mouse with seizures was that the caudate/putamen, substantia nigra, hypothalamus and cerebellum showed almost no significant change (Fig. 1B1,3,5). Furthermore, the vestibular nuclei and posterior colliculus, presumably related to the triggering mechanisms of the seizurO 5, showed normal labeling after seizures (Fig. 1B4,5).
bolic rate in the normal state unexpectedly showed a decreased rate on seizures. Firstly, the thalamic, in particular medial and ventral, nuclei and central gray which were specific or nonspecific showed remarkably decreased densities after seizures (Fig. 1B2,3). Secondly, several interstitial nuclei such as the zona incerta and Cajal's interstitial nucleus were lightly labeled (Fig. 1B2_4). Furthermore, the tegmentum, mesencephalic central gray and locus coeruleus also showed decreased radiolabeling (Fig. 1B4,5). Additionally, the posterior cingulate cortex and colliculus anterior showed a lower optical density
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Fig. 2. [14C]Deoxyglucose autoradiographs of coronal sections and cresyl violet-stained Nissl sections of E1 mouse brains. The autoradiographs of the t4C standards are also visualized. A: sections with no seizure. B: sections with 3 abortive seizures. C: Nissl sections adjacent to the sections in B. SEP, septum; CA3, hippocampal CA3; FD, fascia dentata; Sb, subiculum; other abbreviations are in Fig. 1.
362 In some circumstances an E1 mouse develops abortive seizures and exhibits some localized and isolated paroxysmal discharges in the EEG, which are identical with those observed at the onset of full seizures~L Accordingly, the discharges probably indicate the existence of an epileptic focus. So it is valuable to investigate glucose utilization in an abortive seizure. In an E 1 mouse with 3 abortive seizures during the 40 min after 2-DG administration, a small but significant change was found in the hippocampal area. A small area spreading over the unilateral CA l, CA3, fascia dentata and subibulum was more densely labeled compared with normal (Fig. 2B3). Radiolabeling patterns in such regions as the septum, entorhinal cortex, thalamic nuclei and amygdala which closely connected with the hippocampus and associated areas, were identical with the normal pattern (Fig. 2B). The size and feature of the area showing a higher density were variable and not discrete, because of variable features of abortive seizures. However, it can be presumed that this area may be the epileptic focus in the E1 mouse. The alterations of the radiolabeling in the E l mouse brain described above were the sum total of all the events during the 40 min after 2-DG administration, including convulsions and even recovery processes. However, the increase in the radiolabeling clearly indicates that of the local glucose utilization in the brain tissues. The increases in local glucose utilization were demonstrated in a penicillin cortical focus2,3 or the kindled amygdala and related structures ~. Furthermore, in the mutant mouse tottering with focal seizures, increased metabolic activities in some brainstem structures have been reported 9. According to the dense radiolabeling in the hippocampus and associated areas, it can be assumed that in those areas abnormal excitation or paroxysmal discharges originate in seizures with the increase of local metabolic rate instead of hypoxemic damages. Later on in developing seizures, abnormal excitation propagates to the en-
tire hippocampus, neocortex and other regions. On the other hand, neither the basal ganglia supposedly involved in the propagation of epileptic discharges 7, nor the cerebellum that might inhibit or modify the seizure4, is affected by the abnormal excitation. As stated above, another important problem has arisen from lightly labeled areas such as the thalamic nuclei and others. In human epilepsy, some hypometabglic zones were reported by emission tomography, though during the interictal period 8. At present we cannot conclude whether the lower metabolic activities in those areas were caused by any neuronal inhibitory mechanism or any circulatory disturbance. However, those areas at least do not participate actively in developing seizures of the mouse. These data are different from the results in electroconvulsions where the thalamus, striatum, reticular formation and cerebellum showed glucose utilization I. Our animal model exhibits tonicclonic convulsions, but the generalization mechanism of the abnormal discharges associated with them is unlikely to involve either the extrapyramidal system or the 'centrencephalic system' of Penfield and Jasper 1~which includes the non-specific thalamic nuclei. In conclusion, the results obtained in this report provide us with very important data for understanding the mechanism of idiopathic human epilepsy.
1 Blackwood, D. H. R., Kapoor, V. and Martin, M. J., Regional changes in cerebral glucose utilization associated with amygdaloid kindling and electroshock in the rat,
Brain Research, 224 (1981) 204~ 208. 2 Collins, R. C., Use of cortical circuits during focal penicillin seizures: an autoradiographic study with [14C]deo-
This work was partially supported by grantsin-aid for General Project Research (Animal Model for H u m a n Diseases, 33902) from the Ministry of Education, Science and Culture; and by Grant 80-11-04, from the National Center for Nervous, Mental and Muscular Disorders ( N C N M M D ) of the Ministry of Health and Welfare, Japan. We thank Mr. S. Niibe and Mr. M. Okazaki for their care of the mice, Mr. K. Kato for his photographic work, Mr. R. Nonaka for his collaboration in autoradiographic work, and Miss Y. Fujii for typing the manuscript.
363 xyglucose, Brain Research, 150 (1978) 487-502. 3 Collins, R. C., Kennedy, C., Sokoloff, L. and Plum, F., Metabolic anatomy of focal motor seizures, Arch. Neurol., 33 (1976) 536-542. 4 Cooper, I. S., Riklan, M. and Snider, R. S (Eds.), The Cerebellum, Epilepsy, and Behavior, Plenum Press, New York, 1974, pp. 11%171. 5 Imaizumi, K., Ito, S., Kutsukake, G., Takizawa, T., Fujiwara, K. and Tsuchikawa, K., Epilepsy-like anomaly of mice, Exp. Anita. (Jap.), 8 (1959) 6-10. 6 Imaizumi, K. and Nakano, T., Mutant Stocks. Strain: El, Mouse Newslett., 31 (1964) 57. 7 Jasper, H. H., Wards, A. A. and Pope, A (Eds.), Basic Mechanisms of the Epilepsies, Little, Brown, Boston, 1969, pp. 43(~432. 8 Kuhl, D. E., Engel, Jr., J., Phelps, M. E. and Selin, C., Epileptic patterns of local cerebral metabolism and perfusion in humans determined by emission computed tomography ofl8FDG and 13NH3,Ann. Neurol., 8 (1980) 348360. 9 Noebels, J. L. and Sidman, R. L., Inherited epilepsy: spike-wave and focal motor seizures in the mutant mouse tottering, Science, 204 (1979) 1334-1336. 10 Nonaka, R., Nakamoto, Y. and Suzuki, J., Distribution of 2-deoxy-D-[1Jac]-glucose (2DG) in normal and epileptic mice brains, Jap. J. Neuropsychopharmacol., 2 (1980) 41%423. 11 Penfield, W. and Jasper, H., Epilepsy and the Functional
Anatomy of the Human Brain, Little, Brown, Boston, 1954. 12 Sidman, R. L., Angevine, Jr., J. B. and Taber Pierce, E., Atlas of the Mouse Brain and Spinal Cord., Harvard Univ. Press, Cambridge, MA, 1971. 13 Sokoloff, L., Reivich, M., Kennedy, C., Des Rosiers, M. H., Patlak, C. S., Pettigrew, K. D., Sakuraka, O. and Shinohara, M., The [lac]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat, J. Neurochem., 28 (1977) 897- 916. 14 Suzuki, J., Paroxysmal discharges in the electroencephalogram of the E1 mouse, Experientia, 32 (1976) 336-337. 15 Suzuki, J. and Nakamoto, Y., Seizure patterns and electroencephalograms of E1 mouse, Electroenceph. clin. Neurophysiol., 43 (1977) 29%311. 16 Suzuki, J., Nakamoto, Y. and Nakayama, S., Distribution of 2-deoxy-D-[1J4C]-glucose (2DG)* in E1 mouse brain before and during seizures, Folia Psychiat. Neurol. Jap., 35 (1981) 372-373. 17 Suzuki, J., Nakamoto, Y., Nakayama, S. and Shinkawa, Y., Identification of abnormally excited region due to epileptic seizure of E 1 mouse by 2-DG method, Neurosci. Lett., Suppl. 6 (1981) $46. 18 Suzuki, J., Nonaka, R. and Nakamoto, Y., 2-Deoxyglucose uptake in the brain of a mutant epileptic mouse, In Abstr. 12th Epilepsy International Symposium, 1980, p. 13.
Brain Research, 266 (1983) 35%363 Elsevier Biomedical Press
Local cerebral glucose utilization in epileptic seizures of the mutant El mouse J I R O S U Z U K I , Y U R I E N A K A M O T O and Y O S H I H I R O S H I N K A W A
Division of Neurophysiology, Psychiatric Research Institute of Tokyo 2-1-8, Setagaya-ku, Tokyo, 156 (Japan) (Accepted D e c e m b e r 28th, 1982)
Key words: epilepsy -- E 1 m.ouse -- 2-deoxyglucose - h i p p o c a m p u s - focus - neocortex - excitation - brainstem
The neural p a t h w a y a n d the focus o f the epileptic seizure o f m u t a n t E1 mice were studied by the [14C]2-deoxyglucose technique. In the mice with full t o n i ~ c l o n i c seizure, the entire neocortex and h i p p o c a m p u s showed a remarkably increased m e t a b o l ic rate. By contrast, a lower metabolic rate was evident in the thalamic nuclei, central gray, locus coeruleus and some interstitial nuclei. The epileptic focus in E 1 mice p r e s u m a b l y exists in the h i p p o c a m p u s .
Paroxysmal neural activities in the brain With epileptic seizures could be expected to be accompanied by corresponding changes in local metabolic ratO 3. We have now looked for the neural pathway and the focus involved in the seizure of E 1 mice, an inbred mutant strain susceptible to epilepsy, using the [~4C]2-deoxy-Dglucose (2-DG) method for measuring local cerebral glucose utilization. The E1 mouse is an excellent model of hereditary or idiopathic epilepsy: it was discovered in 19545, registered internationally in 19646, and established electroencephalographically as an epilepsy model in 197614. Preliminary reports of this research were presented at the Epilepsy International Symposium ~8, and other occasions 16,~7. Further quantitative details will be presented elsewhere. About 30 El mice studied were adult o f F 65 to 71, which were kept in our animal center. Radioactive samples of 2-DG (specific activity 58.5 m C i / m m o l ) were obtained from Radiochemical Center, Amersham, and preparations of 3.5 ~Ci/25 g of body weight in physiological saline were administered via the jugular vein. During 40 min after 2-DG administration, a mouse was given seizure-inducing stimulation and then sacrificed. The conditions for provoking seizure and of applying 2-DG to a mouse were reported previously~°,~L Briefly, our method for inducing seizures consists of two steps: observing the mice 0006-8993 / 83/0000- 0000/$03.00 © 1983 Elsevier Science Publishers
on the metal mesh for 3 min and then tossing them up in the air about 10 cm ~5. The radioactivity (RA) in the blood following i.v. administration was 1.%3.3% of the injected RA at 40 min after the injection. 2-DG level in the brain after i.v. administration reached the highest level (about 1.9%) within 5 min, which was maintained for 60 min and thereafter gradually decreased. The time course and the level of concentrations ( d p m / m g of tissues) of 2-DG in the brains of both E1 and D D Y mice showed similar results l°. Based on these facts, all the E1 and control mice used were executed 40 min after the administration of 2-DG. The frozen brain was serially sectioned at 20 #m, mainly in a frontal or horizontal plane. These sections and a set of [~4C]methyl methacrylate standards (Amersham) were placed on X-ray film for a 2 week exposure period. For the location of a nucleus, positive identification was made with the aid of an adjacent histological section stained with cresyl violet, and was referred to the atlas by Sidman et al. 12 In the normal freely moving state, there was no significant difference between autoradiographs of an E1 mouse and a control D D Y mouse. In the E1 mice which exhibited full tonic-clonic seizures twice or three times during 40 min after 2-DG administration, the findings were re-
360 whole hippocampus and associated areas (Fig. 1B2,3). The pyriform cortex, entorhinal cortex and amygdala partially showed a higher density in the seizure mouse (Fig. 1B~_3). By contrast, various parts of the brain which had a higher meta-
markable. As shown in Fig. 1Bf_3, the entire neocortex of the seizure mouse demonstrated a very dense radiolabeling, namely a higher metabolic rate, compared with the normal. The most striking increase of density was observed in the
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Fig. 1. [14C]Deoxyglucose autoradiographs of coronal sections and cresyl violet-stained Nissl sections of El mouse brains. The autoradiographs of the 14C standards are also visualized. A: sections with no seizure. B: sections with 3 full seizures. C: N issl sections adjacent to the sections in B. CER, neocortex; C/P, caudate/putamen; PYR, pyriform cortex; HYP, hypothalamus; HIP, hippocampus; TH, thalamus; AMY, amygdala; ZI, zona incerta; CING, cingulate cortex; COL. A; anterior colliculus; INT. C., Cajal's interstitial nucleus; ER, entorhinal cortex; TEG, tegmentum; SN, substantia nigra; COL. P, posterior colliculus; MCG, mesencephalic central gray; CEL, cerebellum; VES, vestibular nucleus; LC, locus coeruleus.
361 compared with normal (Fig. 1B3). In an E1 mouse with full seizures it is very interesting that, in short, the mantle parts of the brain showed increased radiolabeling, while the central parts showed decreased radiolabeling. Another interesting feature of an E1 mouse with seizures was that the caudate/putamen, substantia nigra, hypothalamus and cerebellum showed almost no significant change (Fig. 1B1,3,5). Furthermore, the vestibular nuclei and posterior colliculus, presumably related to the triggering mechanisms of the seizurO 5, showed normal labeling after seizures (Fig. 1B4,5).
bolic rate in the normal state unexpectedly showed a decreased rate on seizures. Firstly, the thalamic, in particular medial and ventral, nuclei and central gray which were specific or nonspecific showed remarkably decreased densities after seizures (Fig. 1B2,3). Secondly, several interstitial nuclei such as the zona incerta and Cajal's interstitial nucleus were lightly labeled (Fig. 1B2_4). Furthermore, the tegmentum, mesencephalic central gray and locus coeruleus also showed decreased radiolabeling (Fig. 1B4,5). Additionally, the posterior cingulate cortex and colliculus anterior showed a lower optical density
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Fig. 2. [14C]Deoxyglucose autoradiographs of coronal sections and cresyl violet-stained Nissl sections of E1 mouse brains. The autoradiographs of the t4C standards are also visualized. A: sections with no seizure. B: sections with 3 abortive seizures. C: Nissl sections adjacent to the sections in B. SEP, septum; CA3, hippocampal CA3; FD, fascia dentata; Sb, subiculum; other abbreviations are in Fig. 1.
362 In some circumstances an E1 mouse develops abortive seizures and exhibits some localized and isolated paroxysmal discharges in the EEG, which are identical with those observed at the onset of full seizures~L Accordingly, the discharges probably indicate the existence of an epileptic focus. So it is valuable to investigate glucose utilization in an abortive seizure. In an E 1 mouse with 3 abortive seizures during the 40 min after 2-DG administration, a small but significant change was found in the hippocampal area. A small area spreading over the unilateral CA l, CA3, fascia dentata and subibulum was more densely labeled compared with normal (Fig. 2B3). Radiolabeling patterns in such regions as the septum, entorhinal cortex, thalamic nuclei and amygdala which closely connected with the hippocampus and associated areas, were identical with the normal pattern (Fig. 2B). The size and feature of the area showing a higher density were variable and not discrete, because of variable features of abortive seizures. However, it can be presumed that this area may be the epileptic focus in the E1 mouse. The alterations of the radiolabeling in the E l mouse brain described above were the sum total of all the events during the 40 min after 2-DG administration, including convulsions and even recovery processes. However, the increase in the radiolabeling clearly indicates that of the local glucose utilization in the brain tissues. The increases in local glucose utilization were demonstrated in a penicillin cortical focus2,3 or the kindled amygdala and related structures ~. Furthermore, in the mutant mouse tottering with focal seizures, increased metabolic activities in some brainstem structures have been reported 9. According to the dense radiolabeling in the hippocampus and associated areas, it can be assumed that in those areas abnormal excitation or paroxysmal discharges originate in seizures with the increase of local metabolic rate instead of hypoxemic damages. Later on in developing seizures, abnormal excitation propagates to the en-
tire hippocampus, neocortex and other regions. On the other hand, neither the basal ganglia supposedly involved in the propagation of epileptic discharges 7, nor the cerebellum that might inhibit or modify the seizure4, is affected by the abnormal excitation. As stated above, another important problem has arisen from lightly labeled areas such as the thalamic nuclei and others. In human epilepsy, some hypometabglic zones were reported by emission tomography, though during the interictal period 8. At present we cannot conclude whether the lower metabolic activities in those areas were caused by any neuronal inhibitory mechanism or any circulatory disturbance. However, those areas at least do not participate actively in developing seizures of the mouse. These data are different from the results in electroconvulsions where the thalamus, striatum, reticular formation and cerebellum showed glucose utilization I. Our animal model exhibits tonicclonic convulsions, but the generalization mechanism of the abnormal discharges associated with them is unlikely to involve either the extrapyramidal system or the 'centrencephalic system' of Penfield and Jasper 1~which includes the non-specific thalamic nuclei. In conclusion, the results obtained in this report provide us with very important data for understanding the mechanism of idiopathic human epilepsy.
1 Blackwood, D. H. R., Kapoor, V. and Martin, M. J., Regional changes in cerebral glucose utilization associated with amygdaloid kindling and electroshock in the rat,
Brain Research, 224 (1981) 204~ 208. 2 Collins, R. C., Use of cortical circuits during focal penicillin seizures: an autoradiographic study with [14C]deo-
This work was partially supported by grantsin-aid for General Project Research (Animal Model for H u m a n Diseases, 33902) from the Ministry of Education, Science and Culture; and by Grant 80-11-04, from the National Center for Nervous, Mental and Muscular Disorders ( N C N M M D ) of the Ministry of Health and Welfare, Japan. We thank Mr. S. Niibe and Mr. M. Okazaki for their care of the mice, Mr. K. Kato for his photographic work, Mr. R. Nonaka for his collaboration in autoradiographic work, and Miss Y. Fujii for typing the manuscript.
363 xyglucose, Brain Research, 150 (1978) 487-502. 3 Collins, R. C., Kennedy, C., Sokoloff, L. and Plum, F., Metabolic anatomy of focal motor seizures, Arch. Neurol., 33 (1976) 536-542. 4 Cooper, I. S., Riklan, M. and Snider, R. S (Eds.), The Cerebellum, Epilepsy, and Behavior, Plenum Press, New York, 1974, pp. 11%171. 5 Imaizumi, K., Ito, S., Kutsukake, G., Takizawa, T., Fujiwara, K. and Tsuchikawa, K., Epilepsy-like anomaly of mice, Exp. Anita. (Jap.), 8 (1959) 6-10. 6 Imaizumi, K. and Nakano, T., Mutant Stocks. Strain: El, Mouse Newslett., 31 (1964) 57. 7 Jasper, H. H., Wards, A. A. and Pope, A (Eds.), Basic Mechanisms of the Epilepsies, Little, Brown, Boston, 1969, pp. 43(~432. 8 Kuhl, D. E., Engel, Jr., J., Phelps, M. E. and Selin, C., Epileptic patterns of local cerebral metabolism and perfusion in humans determined by emission computed tomography ofl8FDG and 13NH3,Ann. Neurol., 8 (1980) 348360. 9 Noebels, J. L. and Sidman, R. L., Inherited epilepsy: spike-wave and focal motor seizures in the mutant mouse tottering, Science, 204 (1979) 1334-1336. 10 Nonaka, R., Nakamoto, Y. and Suzuki, J., Distribution of 2-deoxy-D-[1Jac]-glucose (2DG) in normal and epileptic mice brains, Jap. J. Neuropsychopharmacol., 2 (1980) 41%423. 11 Penfield, W. and Jasper, H., Epilepsy and the Functional
Anatomy of the Human Brain, Little, Brown, Boston, 1954. 12 Sidman, R. L., Angevine, Jr., J. B. and Taber Pierce, E., Atlas of the Mouse Brain and Spinal Cord., Harvard Univ. Press, Cambridge, MA, 1971. 13 Sokoloff, L., Reivich, M., Kennedy, C., Des Rosiers, M. H., Patlak, C. S., Pettigrew, K. D., Sakuraka, O. and Shinohara, M., The [lac]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat, J. Neurochem., 28 (1977) 897- 916. 14 Suzuki, J., Paroxysmal discharges in the electroencephalogram of the E1 mouse, Experientia, 32 (1976) 336-337. 15 Suzuki, J. and Nakamoto, Y., Seizure patterns and electroencephalograms of E1 mouse, Electroenceph. clin. Neurophysiol., 43 (1977) 29%311. 16 Suzuki, J., Nakamoto, Y. and Nakayama, S., Distribution of 2-deoxy-D-[1J4C]-glucose (2DG)* in E1 mouse brain before and during seizures, Folia Psychiat. Neurol. Jap., 35 (1981) 372-373. 17 Suzuki, J., Nakamoto, Y., Nakayama, S. and Shinkawa, Y., Identification of abnormally excited region due to epileptic seizure of E 1 mouse by 2-DG method, Neurosci. Lett., Suppl. 6 (1981) $46. 18 Suzuki, J., Nonaka, R. and Nakamoto, Y., 2-Deoxyglucose uptake in the brain of a mutant epileptic mouse, In Abstr. 12th Epilepsy International Symposium, 1980, p. 13.