Search

This study aimed to evaluate genotype-phenotype correlations of Parkinson’s disease (PD) patients with phospholipase A2 group V (PLA2G6) variants. We analyzed the DNA of 798 patients with PD, including 78 PD patients reported previously, and 336 in-house controls. We screened the exons and exon-intron boundaries of PLA2G6 using the Ion Torrent system and Sanger method. We identified 21 patients with 18 rare variants, such that 1, 9, and 11 patients were homozygous, heterozygous, and compound heterozygous, respectively, with respect to PLA2G6 variants. The allele frequency was approximately equal between patients with familial PD and those with sporadic PD. The PLA2G6 variants detected frequently were identified in the early-onset sporadic PD group. Patients who were homozygous for a variant showed more severe symptoms than those who were heterozygous for the variant. The most common variant was p.R635Q in our cohort, which was considered a risk variant for PD. Thus, the variants of PLA2G6 may play a role in familial PD and early-onset sporadic PD.

Freezing of gait (FOG) is one of the typical locomotion disorders associated with Parkinsonism, and is described as the inability to move the feet despite an attempt to walk. The fear of falling over and other symptoms of FOG can be distressing to patients. Considering conventional external cues and physical therapy, it is necessary for Parkinsonism patients suffering from FOG to swing the body laterally and rhythmically. The purpose of this study is to develop a wearable system that can assist rhythmical and lateral swing, and to validate the performance of the system in preventing FOG by conducting a gait experiment on a Parkinsonism patient. To develop this system, we simulated lateral swing in the standing position based on features of Parkinsonism and defined a mechanism and appropriate force configurations for the system. A power unit at the back of the waist transmits a cyclic force to the chest through a link in the frontal plane. A gait experiment was performed on a Parkinsonism patient with FOG to confirm the reduction in duration time and number of steps of turning. The result showed that the cyclic assistance of the system and gait cycle were harmonized, and the developed system decreased duration time and number of steps during turning by half. In addition, Pre-FOG, i.e., transient small stepping gait, occurred when turning without using the system, while it did not occur during and immediately after the use of the system. These results suggest that the developed system is effective in preventing occurrences of FOG by providing lateral and cyclic force to the upper body.

Background Mutations in the microtubule associated protein tau ( MAPT ) and progranulin ( PGRN ) have been identified in several neurodegenerative disorders, such as frontotemporal lobar degeneration (FTLD), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). Recently, C9orf72 repeat expansion was reported to cause FTLD and amyotrophic lateral sclerosis (ALS). To date, no comprehensive analyses of mutations in these three genes have been performed in Asian populations. The aim of this study was to investigate the genetic and clinical features of Japanese patients with MAPT , PGRN , or C9orf72 mutations. Methods MAPT and PGRN were analyzed by direct sequencing and gene dosage assays, and C9orf72 repeat expansion was analyzed by repeat-primed PCR in 75 (48 familial, 27 sporadic) Japanese patients with FTLD, PSP, or CBS. Results We found four MAPT mutations in six families, one novel PGRN deletion/insertion, and no repeat expansion in C9orf72 . Intriguingly, we identified a de novo MAPT p.S285R mutation. All six patients with early-onset PSP and the abnormal eye movements that are not typical of sporadic PSP had MAPT mutations. The gene dosages of MAPT and PGRN were normal. Discussion MAPT p.S285R is the first reported de novo mutation in a sporadic adult-onset patient. MAPT mutation analysis is recommended in both familial and sporadic patients, especially in early-onset PSP patients with these abnormal eye movements. Although PGRN and C9orf72 mutations were rare in this study, the PGRN mutation was found in this Asian FTLD. These genes should be studied further to improve the clinicogenetic diagnoses of FTLD, PSP, and CBS.

SNCA duplication is a recognized cause of familial Parkinson's disease (PD). We aimed to explore the genetic and clinical variability in the disease manifestation. Molecular characterization was performed using real-time PCR, SNP arrays, and haplotype analysis. We further studied those patients who were found to harbor SNCA duplication with olfactory function tests, polysomnography, and PET. We identified four new families and one sporadic patient with SNCA duplication. Eleven symptomatic patients from these four families presented with parkinsonism, of which three subsequently developed dementia. The lifetime estimate of overall penetrance was 43.8%. FDG-PET study of symptomatic patients showed hypometabolism in the occipital lobe, whereas asymptomatic carriers of SNCA duplication demonstrated normal glucose metabolism. Symptomatic patients showed abnormal olfactory function and polysomnography and asymptomatic carriers showed normal results. The clinical features of SNCA duplication include parkinsonism with or without dementia. Asymptomatic carriers displayed normal test results with the eldest individual aged 79 years; thus, even a carrier of SNCA duplication may escape the development of PD. This difference in age-associated penetrance may be due to the genetic background or environmental exposures. Further studies of SNCA duplication carriers will help identify disease-modifiers and may open novel avenues for future treatment.

Objective Recently, genomic multiplications of α-synuclein gene (SNCA) have been reported to cause hereditary early-onset parkinsonism. The objective of this study was to assess the frequency of SNCA multiplications among autosomal dominant hereditary Parkinson's disease (ADPD). Methods We screened 113 ADPD probands and 200 sporadic PD cases by quantitative polymerase chain reaction and confirmed SNCA multiplications by flurorescence in situ hybridization (FISH) and comparative genomic hybridization array. Results Two families (two patients from Family A and one from Family B) with SNCA duplication were identified among ADPD patients. Even though they had the same SNCA duplication, one patient had dementia. Because there was exactly the same difference between the regions originated from each patient, the finding suggests that the phenotype of SNCA multiplication may be also influenced by the range of duplication region. We also detected asymptomatic carriers in the families of both patients. Interestingly, the penetrance ratio was 33.3% (2/6) in one kindred, indicating that the ratio was very much lower than expected. Interpretation These two newly identified Japanese patients with SNCA duplication and the five previously identified American and European families with SNCA triplication or duplication mutations indicate that the incidence of SNCA multiplication may be more frequent than previously estimated. Ann Neurol 2006

The importance of enhanced glutamatergic neurotransmission in the basal ganglia and related structures has recently been highlighted in the development of Parkinson's disease. The pedunculopontine tegmental nucleus (PPN) is the major origin of excitatory, glutamatergic input to dopaminergic nigrostriatal neurons of which degeneration is well known to cause Parkinson's disease. Based on the concept that an excitatory mechanism mediated by glutamatergic neurotransmission underlies the pathogenesis of neurodegenerative disorders, we made an attempt to test the hypothesis that removal of the glutamatergic input to the nigrostriatal neurons by PPN lesions might prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the macaque monkey. The PPN was lesioned unilaterally with microinjection of kainic acid, and, then, MPTP was administered systemically. In these monkeys, the degree of parkinsonian motor signs was behaviourally evaluated, and the histological changes in the dopaminergic nigrostriatal system were analysed by means of tyrosine hydroxylase immunohistochemistry. The present results revealed that nigrostriatal cell loss and parkinsonian motor deficits were largely attenuated in the MPTP-treated monkey group whose PPN had been lesioned, compared with the control, MPTP-treated monkey group with the PPN intact. This clearly indicates that the onset of MPTP neurotoxicity is suppressed or delayed by experimental ablation of the glutamatergic input to the nigrostriatal neurons. Such a protective action of excitatory input ablation against nigrostriatal cell death defines evidence that nigral excitation driven by the PPN may be implicated in the pathophysiology of Parkinson's disease.

Among the motor tetrad of Parkinson's disease, akinesia is not easy to define and controversies still exist on the nature of akinesia. In 1972 Barbeau first described pure akinesia without rigidity or tremor responsive to L-dopa therapy, that is, akinesia due to striatal dopamine deficiency. Since 1974, Imai and Narabayashi have described a different type of pure akinesia, unresponsive to L-dopa treatment. This new condition exhibits only the freezing symptom, which is a breakdown of repetitive voluntary movements emerging through festination or suddenly, e.g., freezing of gait, micrographia and inaudible speech. Kinésie paradoxale is always accompanied by this type of akinesia. The author suggested that the main pathological structure of the condition was different from the nigrostriatal dopaminergic system and that the condition was different from Parkinson's disease. Subsequently we expanded our experience to more than 30 patients. All patients were sporadic and slowly progressive, and some had been followed for more than 10 years, still without rigidity or tremor. Slowly progressive supranuclear opthalmoplegia appeared later in several patients, in which progressive supranuclear palsy (PSP) was strongly suggested. Autopsy cases associated with this condition have been reported and pathologically revealed PSP. The nosological position and responsible lesion sites of this condition are discussed.

We report a 67-year-old female with orthostatic and voice tremor. Her orthostatic tremor mainly affected her lower extremities, alternating between antagonist muscle groups at a frequency of 4.4-4.8 Hz. The voice tremor ranged between 4.8 and 8.8 Hz. In this case, the frequency of voice tremor was same as that of orthostatic tremor, suggesting a common origin from a tremor-generating mechanism. These tremors were diagnosed as 'forme fruste' of the essential tremor, not the incipient stage of Parkinson's disease. Medications including clonazepam, perphenazine, Dopa and trihexyphenidyl hydrochloride had no effect on both the orthostatic and voice tremors, but propranolol was somewhat beneficial on voice tremor.

SNCA duplication is a recognized cause of familial Parkinson's disease (PD). We aimed to explore the genetic and clinical variability in the disease manifestation. Molecular characterization was performed using real-time PCR, SNP arrays, and haplotype analysis. We further studied those patients who were found to harbor SNCA duplication with olfactory function tests, polysomnography, and PET. We identified four new families and one sporadic patient with SNCA duplication. Eleven symptomatic patients from these four families presented with parkinsonism, of which three subsequently developed dementia. The lifetime estimate of overall penetrance was 43.8%. FDG-PET study of symptomatic patients showed hypometabolism in the occipital lobe, whereas asymptomatic carriers of SNCA duplication demonstrated normal glucose metabolism. Symptomatic patients showed abnormal olfactory function and polysomnography and asymptomatic carriers showed normal results. The clinical features of SNCA duplication include parkinsonism with or without dementia. Asymptomatic carriers displayed normal test results with the eldest individual aged 79 years; thus, even a carrier of SNCA duplication may escape the development of PD. This difference in age-associated penetrance may be due to the genetic background or environmental exposures. Further studies of SNCA duplication carriers will help identify disease-modifiers and may open novel avenues for future treatment.

The mechanism of abnormal iron accumulation in the substantia nigra (SN) pars compacta of patients with Parkinson's disease (PD) is unknown. To explore this question, we made a hemiparkinsonism model in monkeys by injecting 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the caudate or putamen on one side, and compared iron content in the SN and other basal ganglia structures by histochemistry. The injected side, especially the SN pars compacta, showed a marked increase in iron staining. Our study indicates that an injury to the nigrostriatal system by MPTP injection can induce iron accumulation in the SN.

It is well known that the pathogenesis of Parkinson’s disease is striatal dopamine deficiency subsequent upon degeneration of neurons in the substantia nigra pars compacta (SNc, Albin et al., 1989; DeLong, 1990). Several lines of evidence indicate that the pedunculopontine tegmental nucleus (PPN) is a major origin of excitatory glutamatergic input to nigrostriatal dopamine neurons (Kojima et al., 1997; Scarnati and Florio, 1997; Bezard and Gross, 1998). Recently, the importance of enhanced glutamatergic neurotransmission in the basal ganglia and related structures has been emphasized in the development of Parkinson’s disease (Greenamyre, 1993; Schmidt, 1995; Starr, 1995; Lange et al., 1997). Based on the previous idea that an excitatory mechanism mediated by glutamatergic neurotransmission is closely associated with the onset of neurodegenerative disorders (Choi, 1988; Olney, 1988, 1989; Klockgether and Turski, 1989), we tested the hypothesis that ablation of the glutamatergic input derived from the PPN might prevent nigrostriatal cell death and parkinsonian motor signs that could be induced by the dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

Unexpectedly widespread dopaminergic innervation has been recognized in the primate cerebral cortex. The cortical dopaminergic fibers are distributed throughout the frontal-tooccipital extent, with the highest density in the prefrontal and motor-related areas of the frontal lobe.1-10Previous anatomical studies have shown that multiple motor-related areas of the frontal lobe, such as the primary motor cortex (MI), the premotor cortex (PM), and the supplementary motor area (SMA), contain dopaminergic fibers.1–3,7,8,10 The dopaminergic innervation of the motor-related areas is diffuse, involving all cortical layers.3,7,8,10 On the other hand, the cortical dopaminergic fibers as a whole arise from the three catecholaminergic cell groups—A8, A9, and A 10—that are located in the ventral mesencephalon.3 It has been reported that the cells of origin of the mesocortical dopamine projections to the dorsal frontal cortex, including the motor-related areas, are distributed predominantly in the dorsal aspects of the A8–A10 complex.11,12 In primates, the dorsal components of these catecholaminergic cell groups largely correspond to the dorsal part of the retrorubral area, pars gamma (i e, the dorsal tier) of the substantia nigra pars compacta, and the parabrachial pigmented nucleus of the ventral tegmental area, respectively. Given that subpopulations of dopaminergic neurons in such dorsal components may issue axon collaterals to both the frontal cortex and the striatum (for data in the rat, see refs.13,15), it is most likely that at least part of the dopaminergic fibers in the motor-related areas are affected in Parkinson’s disease which is well known to be caused by the extensive loss of dopaminergic nigrostriatal neurons.

Pure akinesia is a disorder characterized by profound freezing in the absence of rigidity or tremor that is not improved by levodopa therapy. We report two cases of pure akinesia who developed obsessive-compulsive-disorder- (OCD-) like behavior during their illness. Although the pathophysiological mechanism underlying freezing is unclear, the coexistence of pure akinesia and OCD-like behavior suggests that both symptoms have a common pathological basis in these two cases, presumably damage to the pallidum.

To reveal the somatotopy of the pedunculopontine tegmental nucleus that functions as a brainstem motor center, we examined the distribution patterns of corticotegmental inputs from the somatic motor areas of the frontal lobe in the macaque monkey. Based on the somatotopical map prepared by intracortical microstimulation, injections of the anterograde tracers, biotinylated dextran amine and wheat germ agglutinin-conjugated horseradish peroxidase, were made into the following motor-related areas: the primary motor cortex, the supplementary and presupplementary motor areas, the dorsal and ventral divisions of the premotor cortex, and the frontal eye field. Data obtained from the present experiments were as follows: (i) Corticotegmental inputs from orofacial, forelimb, and hindlimb representations of the primary motor cortex tended to be arranged orderly from medial to lateral in the pedunculopontine tegmental nucleus. However, the distribution areas of these inputs considerably overlapped; (ii) The major input zones from distal representations of the forelimb and hindlimb regions of the primary motor cortex were located medial to those from their proximal representations, although there was a substantial overlap between the distribution areas of distal versus proximal limb inputs; (iii) The main terminal zones from the forelimb regions of the primary motor cortex, the supplementary and presupplementary motor areas, and the dorsal and ventral divisions of the premotor cortex appeared to overlap largely in the mediolaterally middle aspect of the pedunculopontine tegmental nucleus; and (iv) Corticotegmental input from the frontal eye field was scattered over the pedunculopontine tegmental nucleus. Thus, the present results indicate that the pedunculopontine tegmental nucleus is likely to receive partly separate but essentially convergent cortical inputs not only from multiple motor-related areas representing the same body part, but also from multiple regions representing diverse body parts. This suggests that somatotopical representations are intermingled rather than segregated in the pedunculopontine tegmental nucleus.

We report the toxic effects of 3,4-dimethoxyphenylethylamine (DMPEA), and tetrahydropapaverine (THP) on the rat nigrostriatal system; THP is a tetrahydroisoquinoline compound which may be derived from DMPEA by conjugation of DMPEA and its oxidative metabolite, dimethoxyphenylacetaldehyde; both are potent inhibitors of mitochondrial complex I. These compounds were introduced to the unilateral caudate-putamen of male Sprague-Dawley rats over 7 days using a 200-microl mini-osmotic pump. Striatal dopamine on the injected side showed a significant decrease to 86% of the non-injected side after 16.55 micromol/7 days infusion of DMPEA, and to 73% of the non-injected side after 7.90 micromol/7 days of THP infusion; as the non-injected side dopamine also reduced in the THP-injected rats, dopamine on the injected side was 55% of the saline control. Tyrosine hydroxylase (TH)-positive nigral neurons were decreased to 76% of the non-injected side after 16.55 micromol/7 days infusion of DMPEA and to 77% after 7.90 micromol/7 days of THP infusion. Dimethoxyphenyl-tetrahydroisoquinoline compounds appear to be potent nigral neurotoxins.

Dopaminergic nigrostriatal neurons, degeneration of which causes Parkinson's disease, are known to receive excitatory input almost exclusively from the pedunculopontine tegmental nucleus (PPN). We report here that excitotoxic lesions of the PPN produce abnormal motor signs relevant to hemiparkinsonism in the macaque monkey. Under the guidance of extracellular unit recordings, the electrophysiologically identified PPN was injected unilaterally with kainic acid. These PPN-lesioned monkeys exhibited mild to moderate levels of flexed posture and hypokinesia in the upper and lower limbs contralateral to the lesion. In most of the monkeys, such pathophysiological events were gradually improved and became stationary in 1-2 weeks. The hemiparkinsonian symptoms observed after PPN destruction might be ascribed to a decrease in nigrostriatal neuron activity due to excitatory input ablation.

Iron is increased in the substantia nigra of patients with Parkinson's disease, but the mechanism of its accumulation is unknown. We report the distribution of ferritin in the basal ganglia of hemiparkinsonian monkeys made by MPTP. We stereotactically injected MPTP unilaterally into the caudate nucleus of four monkeys, and the substantia nigra and the basal ganglia regions were stained for L-ferritin by an immunohistochemical method. The ferritin immuno-staining was most intense in the pallidum and the pars reticulata of the substantia nigra on both injected and non-injected sides. No significant difference was noted in the immunostaining for ferritin in the pars compacta of the substantia nigra between the injected and the non-injected side. Iron was increased in the pars compacta of the substantia nigra of this hemiparkinsonian monkeys in our previous study. Normal ferritin immunostaining on the injected side would indicate that iron accumulation is not related to altered metabolism of L-ferritin in this model.

Iron is increased in the substantia nigra of patients with Parkinson’s disease (PD). The mechanism of its accumulation, however, remains to be explored. In this study, we stereotactically injected MPTP into the unilateral putamen or caudate nucleus of six monkeys. The substantia nigra and the basal ganglia regions were stained for iron and ferritin by histochemical methods. We found a marked increase in the intensity of iron staining in the pars compacta of the substantia nigra. On the other hand, no significant difference was noted between the injected side and the non-injected side in ferritin steining. Such results suggest that the iron accumulation in this model as well as in PD may be a result of nigral degeneration, but unbalanced increase in iron with respect to the amount of ferritin may contribute to the progression of the disease by inducing oxidative stress.

Apoptosis is a morphologically distinct process of cell death. Recently, non-physiologic agents, such as radiation, toxic substances and drugs, have been found to induce apoptosis. In this study, we report the presence of apoptotic cell death in cultured mesencephalic neurons treated with MPP+ and in the monkey substantia nigra after putaminal injection of MPTP by the TdT-mediated dUTP-biotin nick-end labeling (TUNEL) method. Apoptosis may be an important mechanism of cell death in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) - induced parkinsonism.

Since 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was found to produce symptoms similar to Parkinson’s disease (Langston et al., 1983), toxins with structure similar to MPTP have been hypothesized to result in cell death of mesencephalic dopamine neurons. 1,2,3,4-Tetrahydroisoquinoline (TIQ) has a structure similar to MPTP, and it, and its derivatives exist as endogenous amines in human brain (Ohta et al., 1987; Niwa et al., 1987; Niwa et al., 1989). Toxic properties of TIQ on mitochondria are similar to those of MPP+ (the oxidative product of MPTP) (Suzuki et al., 1988). N-methyltetrahydroisoquinoline (NMTIQ) is formed from TIQ by N-methyltransferase (Naoi et al., 1989a). NMTIQ is oxidized by both type A and B monoamine oxidases, and the N-methylisoquinolinium ion (NMIQ+), the oxidative product, inhibits activities of enzymes related to catecholamine metabolism (Naoi et al., 1989b). NMTIQ and NMIQ+ inhibits complex I activity, similarly to TIQ, and this inhibitory potency of NMIQ+ on complex I activity is stronger than that of MPP+ (Suzuki et al., 1992). Recently, we administered TIQ and its derivatives (NMTIQ and NMIQ+) to monkeys and observed mesencephalic dopamine neurons immunohistochemically. Using light and electron microscopy we found that NMTIQ produces changes in mesencephalic dopamine neurons.

A 9-year-old girl with huge, double arachnoid cysts at the cerebellopontine angle is reported. After a cyst-peritoneal shunt operation, she developed fine, high-frequency gaze nystagmus towards the lesion side combined with coarse, large amplitude nystagmus in the opposite direction, which is the reverse of the Bruns' nystagmus. We call this reverse phenomenon 'inverted' Bruns' nystagmus. As the nystagmus disappeared after a second shunt operation, the nystagmus was presumed to be caused by the cystic lesion.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) elicits selective destruction of nigrostriatal dopamine neurons in human and non-human primates along with clinical symptoms of Parkinson’s disease (Langston et al., 1983; Burns et al., 1983). Systemically administered MPTP is biotransformed into 1-methyl-4-phenylpyridium ion (MPP+), which then enters dopaminergic neurons via the dopamine uptake system to destroy nigral cells.

We studied the oxidation of sparteine in 36 patients with early onset (onset of age 1.5). These findings indicate that the oxidative capacity of sparteine is not defective but reduced in some patients with an earlier onset of Parkinson’s disease, possibly implying that the decreased activity of cytochrome P-450 responsible for the oxidation of sparteine would be a factor to accelerate the onset of the Parkinson’s disease.

A case of metrizamide encephalopathy with persistent consciousness disturbance and extrapyramidal symptoms was reported.

Systemically administered 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), a toxin inducing parkinsonism, is biotransformed into 1methyl-4-.phenylpyridinium ion (MPP+), which then enters dopaminergic neurons via the dopamine uptake system to destroy nigral cells.

Autopsy was performed on a 52 year old man with a 20-year history of neurological symptoms. At autopsy, both a brain stem tumor and a spinal cord tumor were found. These showed the features of pilocytic astrocytoma histologically. A pilocytic astrocytoma was also found in the optic chiasm upon microscopical examination. These three tumors were thought to be multicentric astrocytomas, because there was no continuity among them and no evidence of dissemination or metastasis by any pathway. From a review of the literature, the present case is considered to be an exceedingly rare one because of the multicentric sites of occurrence. Acta Pathol Jpn 39: 664 669, 1989.

The intranuclear organization of divergently projecting neurons of the midbrain raphe in the rat was studied by using double retrograde axonal tracing. Paired injections of the tracers N-[acetyl-3H] WGA and horseradish peroxidase were made within known projection targets of the midbrain raphe (caudate-putamen, amygdala, hippocampus, substantia nigra, and locus coeruleus). After injections of either tracer in the aforementioned targets, retrograde labeled neurons were found mainly ipsilaterally and within midline portions of the dorsal raphe nucleus, its caudal B6 portion, and within the linear and superior central nuclei of the median raphe complex. There are discrete intranuclear distributions of raphe neurons that project to these forebrain and brainstem sites, and there is an overall rostrocaudal topographic order within the raphe with neurons projecting to the neostriatum, amygdala, and substantia nigra residing most rostrally and neurons projecting to the hippocampus and/or locus coeruleus occupying caudal portions of the B6 and superior central nuclei. Such distributions of projection neurons suggest the existence of an “encephalotopic” intranuclear organization within the raphe; that is, each central nervous system structure that receives midbrain raphe projections has its own unique representation within a topographically distinct portion of one or more of the raphe subgroups. These findings suggest an overall functional organization within the midbrain raphe nuclear complex whereby rostral portions are associated with the basal ganglia and related nuclei, and caudal portions relate to the limbic system. An intermediate representation of amygdala-projecting raphe neurons functionally conjoins the two. Collateralized neurons are found within complex zones of overlap in the topographically organized distributions of raphe neurons projecting to functionally related structures.

1. The morphology of dorsal raphe neurons was examined using intracellular injections of horseradish peroxidase (HRP) and the Golgi technique. Light microscopic examination of HRP-labeled projection neurons revealed a neuron type with radiating, poorly branched and sparsely spined dendrites and terminal dendritic thickets. The stem axon of these neurons left the nucleus ventrally but gave off a beaded collateral while still within the parent cell's dendritic domain. Somatodendritic morphology from Golgi-Kopsch stained material coincided with intracellular HRP findings and the dorsal raphe may consist of varieties of one basic morphological type of neuron. 2. Intracellular recordings made during the HRP injection experiments confirmed that stimulation of the ventral medial tegmentum elicited an antidromic action potential and an inhibitory postsynaptic potential in dorsal raphe projection neurons. 3. The order of axonal projections arising from the midbrain raphe nuclei was examined using a double retrograde axonal tracing technique. After paired HRP and [ 3 H] wheat germ agglutinin injections within certain projection targets of the dorsal and median raphe neurons (caudate-putamen, amygdala, hippocampus, substantia nigra and locus coeruleus)), each target structure was found to have its own unique representation within a topographically distinct portion of one or more of the raphe subgroups. Neurons projecting to the caudate-putamen and substantia nigra occupied rather rostral portions. Neurons projecting to the hippocampus and locus coeruleus resided more caudally. Neurons projecting to the amygdala were situated intermediately. Overall, rostrocaudal topography in the intranuclear distributions of raphe projection neurons resulted in the formation of complex overlap zones where collateralized neurons always resided.

Systemically administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is biotransformed into 1-methyl-4-phenylpyridinium ion (MPP + ), which enters dopaminergic neurons via the dopamine uptake system to destroy nigral cells. Either MPP + is retrogradely transported to the cell body after being taken up at the nerve terminals, or the dopamine uptake sites on the cell body and its dendritic processes are responsible for the toxin directly entering the neuron. Using a 200 μl osmotic minipump, we administered 4 mg of MPTP HCl directly into the unilateral caudate nucleus, i.e., the dopamine nerve terminal area, of monkeys for 14 days. Persistent hemiparkinsonism began to appear in a week. Each monkey exhibited a flexed posture and hypokinesia of the contralateral limbs and circling toward the MPTP-treated side. These disturbances developed within 3 months and maintained a plateau for 3 months until the day of sacrifice. After treatment with apomorphine, there appeared a striking circling away from the MPTP-treated side. Selective cell loss in the MPTP-treated side of the substantia nigra pars compacta was found along the entire rostrocaudal extent relative to the untreated side. In conclusion, MPP + uptake only at the dopamine nerve terminals and retrograde axonal transport to the cell body seemed suffcient to destroy nigral dopamine cells in the monkey.