SlOO Clirtical Neurology and Neurosurgery, 94 (Suppl.)(1992) SlOO-SlO2 0 1992 Elsevier Science Publishers B.V. All rights reserved 0303~8467/92/$0.5.00 CNN 00125
On chorea: possible neuronal mechanisms Ichiro Kanazawa Depaninent of Neurology, Institute of Brain Research, University of Tokyo, Tokyo 113 (Japan)
Z&y wor&:
Huntington’s disease; Dopamine; Dopamine receptor
Summary The mechanism of generation of choreic movements is a rather diflicult issue to be elucidated, chiefly due to the lack of a good animal model. Recently we have succeeded to reproduce choreic movements in monkey by using kainic acid lesion of the striatum and the administration of t_-dopa. Based on the morphological and biochemical findings of monkey brains, we proposed the hypothesis for the mechanism of choreic movements to be the presynaptic “activation” of the nigro-striatal dopaminergic pathways rather than the postsynaptic dopaminergic receptors in the striatum. This hypothesis coincide well with the clinical and clinico-pharmacological experience in Huntington’s disease. The possible mechanisms of the dopaminergic “activation” are discussed Introduction Huntington’s disease (HD) is characterized by choreic movements which resemble purposeful voluntary movcments and are difficult to reproduce in animals [l]. Rccently, we have succeeded to induce choreic movements in monkey and investigated the neurotransmitter altcrations in brains [2]. The hypothesis concerning the induction of choreatic movements is discussed. Summary of the chorea monkey model experiment [2] In order to produce choreic movements in monkey (Mucaca sp.), we used the combination of unilateral kainic acid injections into the striatum and the systemic administration of L-dopa. Seven monkeys received kainic acid injections and were treated with L-dopa orally (150300 mg/day). Five monkeys with lesions in the rostra1 dorsolateral striatum showed 4-7 days after the operation choreic movements in the contralateral limbs following L-dopa. In 2 monkeys with a 60% destruction of the rostral striatum, no choreic movements could be induced. The brains of all monkeys were analyzed biochemically for GABA content, choline acetyltransferase (ChAT) and tyrosine hydroxylase (T-OH) activity and Dr doCorrcspondencelo: Professor Dr. I. Kanazawa, Department of Neurology, Institute of Brain Research, University of Tokyo, Tokyo 113. Japan. Tel.: (3) 38156411 ext. 8749; Fax: (3) 3813-2129.
pamine receptor binding in the basal ganglia. Concentrations of GABA, ChAT activity and D, receptor binding did not correlate with the generation of choreic movements. A 50% increase in T-OH activity in the rostraI ventromedial striatum on the lesioned side compared with the control side was found in the choreatic monkeys. Therefore, it is assumed that certain populations of “activated” nigro-striatal dopaminergic neurones which innervate the unlesioned area of the striatum may be more likely to attain a level of activity, induced by t-dopa, sufIicicnt to produce choreic movement in the contralatera1 limbs. These results support the hypothesis that the “activated” dopaminergic components in choreic monkeys are the presynaptic dopaminergic nerve terminals rather than the postsynaptic dopaminergic receptors. Role of the striatal pathology in chorea Based on the pathological characteristics in HD most studies are directed to the striatum. But so far no definite choreic movements were produced. It should be pointed out, however, that in most studies lesions were made electrolytically or thermolytically, which destroyed not only striatal neurons but also nerve terminals belonging to the afferent fibers from the substantia nigra and the cerebral cortex. In HD those striatal afferent fibers are believed to be maintained. In this respect, the striatal lesions by injection of excitotoxic amino acid, kainic acid, into the striatum will be a most suitable tool for this
SlOl
I
CEREBRAL CORTEX
logy in chorea, it is possible to summarize that a “partial” neuronal degeneration in the striatum will be a base of the generation of choreic movements under the condition that the nigro-striatal pathways are intact or relatively spared.
1
STRIATUM
Role of dopamine
r
a( LThal
1 1
GPi/SNr
Fig. 1. Schematic diagram of the circuitry and neurotransmitters of the basal ganglia, originally presented by Alexander and Crutcher [S] with the following modifications. (1) A connection from the striatum to the substantia nigra pars compacta (SNc). There is no doubt that SNc neurones receive direct GABA-ergic input from the striatal neurons onto their long dendrites situated in the pars reticulata (SNr). (2) A connection from the subthalamic nucleus (STN) to SNc. In 1975, we reported that SNc neurones more predominantly receive fibers from !XN neurones than SNr neurones, using the HRP retrograde transporting method [lo].
purpose in terms of pathology and biochemistry in the basal ganglia, because these excitotoxic amino acid does not destroy nerve terminals in the striatum [3]. This means that for the induction of chorea the restoration of the afferent input to the striatum is needed. In the afferents, the nigro-striatal pathways is the most important one. In Pick’s disease without choreatic movements, severe striatal atrophy similar to HD is reported, but accompanied by neuronal loss in the substantia nigra [4]. In fact, in clinical neurology we have never seen choreic movements in combination with nigral degeneration. In our monkey study, no choreatic movements appeared after severe destruction (more than 60%) of the striatum. Choreatic movements appeared especially when the rostra1 putamen wasparZiuZly destroyed. In HD, it is well known that choreic movements usually decline at the later stage when the striatal neurones are totally gone. Therefore, concerning the role of the striatal patho-
in chorea
As mentioned above, the nigro-striatal dopaminergic pathways seem to have an important role in the generation of chorea. indeed, this assumption is strongly supported by biochemical and pharmacological evidence, i.e. the apparently most striking biochemical finding in HD brain is the normal or slightly increased levels of dopamine and its synthesizing enzymes in the striatum and the substantia nigra [5]. In addition, choreic movements are readily suppressed by the administration of neuroleptics. Moreover, some of the subjects at risk for HD manifest choreic movements by the provocative administration of L-dopa [6]. All of the above findings favor the hypothesis that choreic movements are directly related to enhanced (absolutely or relatively) dopaminergic function, especially in the striaturn. Concerning the “enhanced” component of the dopaminergic neuroncs, our monkey experiment demonstrated that the “activated” component was the presynaptic dopaminergic nerve terminals rather than the postsynaptic dopamine receptors [2]. Indeed, in HD brains an increase of dopamine concentration was confirmed although not of the dopamine receptor. Possible mechanisms
for the ‘activation’
of dopamine
neurones
Several mechanisms for the activation of the presynaptic dopaminergic nerve terminals are known. (1) A loss of striatal GABA-ergic inhibitory neurones leads to a disinhibition of the nigral dopaminergic neurones (see Fig. 1, [S] direct pathway). Our monkey model, however, did not support this mechanism, since there was no correlation between GABA-loss in the substantia nigra and the appearance of choreic movements [2]. In addition, GABA in HD brain is not always decreased in the substantia nigra (unpublished data). Therefore, this mechanism is not plausible. (2) A loss of GABA/enkephalin neurones in the striaturn which project to the external segment of the globus pallidus leads to a disinhibition of the external pallidal ncurones. Thus activated pallidal neurones inhibit the subthalamic neurones (see Fig. 1, indirect pathway). Then, suppressed excitatory subthalamic neurones could enhance neurones of the substantia nigra. However, this hypothesis is self-contradictory; if a net function of sub-
s102 thalamic neurones is indeed excitatory, a neuronal activity of nigral dopaminergic neurones should be depressed rather than activated. In fact, different from the GABA antagonist-induced Crossman’s monkey model [9], an autoradiogram using 2-deoxyglucose (2-DG) in our hemi-choreic monkey demonstrated no apparent increase of uptake of 2-DG in the ipsilateral subthalamic nucleus (unpublished data). Therefore, this hypothesis is also unlikely. (3) A loss of neurones in the striatum forces the dopaminergic terminals in the striatum to be re-organized 121. In case of monkey model, certain populations of varicosities on nerve terminals of the nigro-striatal fibers are involved in the kainic acid lesion and lose their partner (dopamine-receptive) neurones, irrespective of their neurotransmitter; GABA, substance P, enkephalin or acetylcholine. Another population of varicosities belonging to the same fibers may be located in the escaped striatum and not involved in the kainic acid lesion. If this is the case, re-organization in the dopaminergic nerve terminals could occur which leads to the compensatory activation of the dopaminergic neurones. In fact, an autoradiogram using 2-DG in our choreic monkeys demonstrated the patchy high intensity areas in and around the kainic acid lesion (unpublished data). Since 2-DG is a marker of activated nerve terminals rather than nerve cells, this coincides very well with the present hypothesis. Although it is difficult to find evidence fort this hypothesis in HD brain, re-organization of the dopaminergic nerve terminals could occur in the striatum of this “chronic”, “progressive” and “degenerative” disorder, i.e. HD.
meeting of the WFN Research Group for Huntington’s Chorea when Prof. Bruyn whispered in my ear, asking “Do you truly want to study HDforer~eer? If so, you could join the group”. To be honest, I had been wondering whether it was wise or not to do research on HD in Japan where the disease is so rare. Professor Bruyn’s whispering, however, triggered a very good idea: since it is so rare, it would be possible to collect all the HD patients in this country! My answer was, therefore, “Yes, I do, Professor”. In the next 12 years, Professor Bruyn was always whispering in my ear “Do you truly. . . ‘!“, and I collected 46 HD families, which is roughly one-tenth of the Japanese HD families. Unfortunately, not yet all, but my work is continuing. I am therefore indebted to Professor Bruyn, for bringing me to the field of HD research, and for giving me the chance to study HD. He has always given me his warmest encouragement. He is my teacher and at the same time he is my “father”. References 1 Bruyn GW. In: Vinken PJ, Bruyn GW (eds.), Handbookof
2 3 4 5 6 7 8 9
Epilogue This paper is dedicated to Professor George W. Bruyn. It was in Fuji in 1981, just before the start of the business
10
Clinical Neurology, Vol. 6. Amsterdam: North-Holland, 1968: 298-378. Kanazawa I, Kimura M, Murata M, Tanaka Y, Cho F. Brain 1990; 113: 509-535. McGeer EG, McGeer PL. Nature 1976; 263: 517-519. Kanazawa I, Kwak S, Sasaki II, Muramoto 0, Mizutani T, Hori A, Nukina N. J Neural Sci 1988; 83: 63-74. Bird ED, Spokes EGS, Iversen LL. Acta Psychiat Stand 1980; 61 (Suppl 280): 63-73. KIawans HL. Goetz CG, Paulson GW, Barbeau A. New EngI J Med 1980; 302: 1090. Melamed E, Hefi F, Bird D. Neurology 1982; 32: 640-644. Alexander GE, Crutcher MD. Trends Neurosci 1990; 13: 266-271. Crossman AR, Sambrook MA, Mitchell IJ, Jackson A, CIarcks CE, Robertson RG, Boyce S. In: Carpenter MB, Jayaraman A. (eds.), The Basis Ganglia II. Structure and Function - Current Concepts. New York: Raven Press, 1987: 377-394. Kanazawa I, Marshall GR, Kelly JS. Brain Res 1976; 115: 485-491
On chorea: possible neuronal mechanisms Ichiro Kanazawa Depaninent of Neurology, Institute of Brain Research, University of Tokyo, Tokyo 113 (Japan)
Z&y wor&:
Huntington’s disease; Dopamine; Dopamine receptor
Summary The mechanism of generation of choreic movements is a rather diflicult issue to be elucidated, chiefly due to the lack of a good animal model. Recently we have succeeded to reproduce choreic movements in monkey by using kainic acid lesion of the striatum and the administration of t_-dopa. Based on the morphological and biochemical findings of monkey brains, we proposed the hypothesis for the mechanism of choreic movements to be the presynaptic “activation” of the nigro-striatal dopaminergic pathways rather than the postsynaptic dopaminergic receptors in the striatum. This hypothesis coincide well with the clinical and clinico-pharmacological experience in Huntington’s disease. The possible mechanisms of the dopaminergic “activation” are discussed Introduction Huntington’s disease (HD) is characterized by choreic movements which resemble purposeful voluntary movcments and are difficult to reproduce in animals [l]. Rccently, we have succeeded to induce choreic movements in monkey and investigated the neurotransmitter altcrations in brains [2]. The hypothesis concerning the induction of choreatic movements is discussed. Summary of the chorea monkey model experiment [2] In order to produce choreic movements in monkey (Mucaca sp.), we used the combination of unilateral kainic acid injections into the striatum and the systemic administration of L-dopa. Seven monkeys received kainic acid injections and were treated with L-dopa orally (150300 mg/day). Five monkeys with lesions in the rostra1 dorsolateral striatum showed 4-7 days after the operation choreic movements in the contralateral limbs following L-dopa. In 2 monkeys with a 60% destruction of the rostral striatum, no choreic movements could be induced. The brains of all monkeys were analyzed biochemically for GABA content, choline acetyltransferase (ChAT) and tyrosine hydroxylase (T-OH) activity and Dr doCorrcspondencelo: Professor Dr. I. Kanazawa, Department of Neurology, Institute of Brain Research, University of Tokyo, Tokyo 113. Japan. Tel.: (3) 38156411 ext. 8749; Fax: (3) 3813-2129.
pamine receptor binding in the basal ganglia. Concentrations of GABA, ChAT activity and D, receptor binding did not correlate with the generation of choreic movements. A 50% increase in T-OH activity in the rostraI ventromedial striatum on the lesioned side compared with the control side was found in the choreatic monkeys. Therefore, it is assumed that certain populations of “activated” nigro-striatal dopaminergic neurones which innervate the unlesioned area of the striatum may be more likely to attain a level of activity, induced by t-dopa, sufIicicnt to produce choreic movement in the contralatera1 limbs. These results support the hypothesis that the “activated” dopaminergic components in choreic monkeys are the presynaptic dopaminergic nerve terminals rather than the postsynaptic dopaminergic receptors. Role of the striatal pathology in chorea Based on the pathological characteristics in HD most studies are directed to the striatum. But so far no definite choreic movements were produced. It should be pointed out, however, that in most studies lesions were made electrolytically or thermolytically, which destroyed not only striatal neurons but also nerve terminals belonging to the afferent fibers from the substantia nigra and the cerebral cortex. In HD those striatal afferent fibers are believed to be maintained. In this respect, the striatal lesions by injection of excitotoxic amino acid, kainic acid, into the striatum will be a most suitable tool for this
SlOl
I
CEREBRAL CORTEX
logy in chorea, it is possible to summarize that a “partial” neuronal degeneration in the striatum will be a base of the generation of choreic movements under the condition that the nigro-striatal pathways are intact or relatively spared.
1
STRIATUM
Role of dopamine
r
a( LThal
1 1
GPi/SNr
Fig. 1. Schematic diagram of the circuitry and neurotransmitters of the basal ganglia, originally presented by Alexander and Crutcher [S] with the following modifications. (1) A connection from the striatum to the substantia nigra pars compacta (SNc). There is no doubt that SNc neurones receive direct GABA-ergic input from the striatal neurons onto their long dendrites situated in the pars reticulata (SNr). (2) A connection from the subthalamic nucleus (STN) to SNc. In 1975, we reported that SNc neurones more predominantly receive fibers from !XN neurones than SNr neurones, using the HRP retrograde transporting method [lo].
purpose in terms of pathology and biochemistry in the basal ganglia, because these excitotoxic amino acid does not destroy nerve terminals in the striatum [3]. This means that for the induction of chorea the restoration of the afferent input to the striatum is needed. In the afferents, the nigro-striatal pathways is the most important one. In Pick’s disease without choreatic movements, severe striatal atrophy similar to HD is reported, but accompanied by neuronal loss in the substantia nigra [4]. In fact, in clinical neurology we have never seen choreic movements in combination with nigral degeneration. In our monkey study, no choreatic movements appeared after severe destruction (more than 60%) of the striatum. Choreatic movements appeared especially when the rostra1 putamen wasparZiuZly destroyed. In HD, it is well known that choreic movements usually decline at the later stage when the striatal neurones are totally gone. Therefore, concerning the role of the striatal patho-
in chorea
As mentioned above, the nigro-striatal dopaminergic pathways seem to have an important role in the generation of chorea. indeed, this assumption is strongly supported by biochemical and pharmacological evidence, i.e. the apparently most striking biochemical finding in HD brain is the normal or slightly increased levels of dopamine and its synthesizing enzymes in the striatum and the substantia nigra [5]. In addition, choreic movements are readily suppressed by the administration of neuroleptics. Moreover, some of the subjects at risk for HD manifest choreic movements by the provocative administration of L-dopa [6]. All of the above findings favor the hypothesis that choreic movements are directly related to enhanced (absolutely or relatively) dopaminergic function, especially in the striaturn. Concerning the “enhanced” component of the dopaminergic neuroncs, our monkey experiment demonstrated that the “activated” component was the presynaptic dopaminergic nerve terminals rather than the postsynaptic dopamine receptors [2]. Indeed, in HD brains an increase of dopamine concentration was confirmed although not of the dopamine receptor. Possible mechanisms
for the ‘activation’
of dopamine
neurones
Several mechanisms for the activation of the presynaptic dopaminergic nerve terminals are known. (1) A loss of striatal GABA-ergic inhibitory neurones leads to a disinhibition of the nigral dopaminergic neurones (see Fig. 1, [S] direct pathway). Our monkey model, however, did not support this mechanism, since there was no correlation between GABA-loss in the substantia nigra and the appearance of choreic movements [2]. In addition, GABA in HD brain is not always decreased in the substantia nigra (unpublished data). Therefore, this mechanism is not plausible. (2) A loss of GABA/enkephalin neurones in the striaturn which project to the external segment of the globus pallidus leads to a disinhibition of the external pallidal ncurones. Thus activated pallidal neurones inhibit the subthalamic neurones (see Fig. 1, indirect pathway). Then, suppressed excitatory subthalamic neurones could enhance neurones of the substantia nigra. However, this hypothesis is self-contradictory; if a net function of sub-
s102 thalamic neurones is indeed excitatory, a neuronal activity of nigral dopaminergic neurones should be depressed rather than activated. In fact, different from the GABA antagonist-induced Crossman’s monkey model [9], an autoradiogram using 2-deoxyglucose (2-DG) in our hemi-choreic monkey demonstrated no apparent increase of uptake of 2-DG in the ipsilateral subthalamic nucleus (unpublished data). Therefore, this hypothesis is also unlikely. (3) A loss of neurones in the striatum forces the dopaminergic terminals in the striatum to be re-organized 121. In case of monkey model, certain populations of varicosities on nerve terminals of the nigro-striatal fibers are involved in the kainic acid lesion and lose their partner (dopamine-receptive) neurones, irrespective of their neurotransmitter; GABA, substance P, enkephalin or acetylcholine. Another population of varicosities belonging to the same fibers may be located in the escaped striatum and not involved in the kainic acid lesion. If this is the case, re-organization in the dopaminergic nerve terminals could occur which leads to the compensatory activation of the dopaminergic neurones. In fact, an autoradiogram using 2-DG in our choreic monkeys demonstrated the patchy high intensity areas in and around the kainic acid lesion (unpublished data). Since 2-DG is a marker of activated nerve terminals rather than nerve cells, this coincides very well with the present hypothesis. Although it is difficult to find evidence fort this hypothesis in HD brain, re-organization of the dopaminergic nerve terminals could occur in the striatum of this “chronic”, “progressive” and “degenerative” disorder, i.e. HD.
meeting of the WFN Research Group for Huntington’s Chorea when Prof. Bruyn whispered in my ear, asking “Do you truly want to study HDforer~eer? If so, you could join the group”. To be honest, I had been wondering whether it was wise or not to do research on HD in Japan where the disease is so rare. Professor Bruyn’s whispering, however, triggered a very good idea: since it is so rare, it would be possible to collect all the HD patients in this country! My answer was, therefore, “Yes, I do, Professor”. In the next 12 years, Professor Bruyn was always whispering in my ear “Do you truly. . . ‘!“, and I collected 46 HD families, which is roughly one-tenth of the Japanese HD families. Unfortunately, not yet all, but my work is continuing. I am therefore indebted to Professor Bruyn, for bringing me to the field of HD research, and for giving me the chance to study HD. He has always given me his warmest encouragement. He is my teacher and at the same time he is my “father”. References 1 Bruyn GW. In: Vinken PJ, Bruyn GW (eds.), Handbookof
2 3 4 5 6 7 8 9
Epilogue This paper is dedicated to Professor George W. Bruyn. It was in Fuji in 1981, just before the start of the business
10
Clinical Neurology, Vol. 6. Amsterdam: North-Holland, 1968: 298-378. Kanazawa I, Kimura M, Murata M, Tanaka Y, Cho F. Brain 1990; 113: 509-535. McGeer EG, McGeer PL. Nature 1976; 263: 517-519. Kanazawa I, Kwak S, Sasaki II, Muramoto 0, Mizutani T, Hori A, Nukina N. J Neural Sci 1988; 83: 63-74. Bird ED, Spokes EGS, Iversen LL. Acta Psychiat Stand 1980; 61 (Suppl 280): 63-73. KIawans HL. Goetz CG, Paulson GW, Barbeau A. New EngI J Med 1980; 302: 1090. Melamed E, Hefi F, Bird D. Neurology 1982; 32: 640-644. Alexander GE, Crutcher MD. Trends Neurosci 1990; 13: 266-271. Crossman AR, Sambrook MA, Mitchell IJ, Jackson A, CIarcks CE, Robertson RG, Boyce S. In: Carpenter MB, Jayaraman A. (eds.), The Basis Ganglia II. Structure and Function - Current Concepts. New York: Raven Press, 1987: 377-394. Kanazawa I, Marshall GR, Kelly JS. Brain Res 1976; 115: 485-491
