Abstract
This light and electron microscopie immunohistochemical quantitative study aimed at determining the state of the dopamine (DA) and serotonin (5-HT) innervations of the internal (GPi) and external (GPe) segments of the pallidum in cynomolgus monkeys (Macaca fascicularis) rendered parkinsonian by systemic injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In contrast to the prominent DA denervation of striatum, the GPi in MPTP monkeys was found to be markedly enriched in DA (TH+) axon varicosities. The posterior sensorimotor region of this major output structure of the basal ganglia was about 8 times more intensely innervated in MPTP monkeys (0.71 ± 0.08 × 106 TH+ axon varicosities/mm3) than in controls (0.09 ± 0.01 × 106). MPTP intoxication also induced a two-fold increase in the density of 5-HT (SERT+) axon varicosities in both GPe and GPi. This augmentation was particularly pronounced anteriorly in the so-called associative and limbic pallidal territories. The total length of the labeled pallidal axons was also significantly increased in MPTP monkeys compared to controls, but the number of DA and 5-HT axon varicosities per axon length unit remained the same in the two groups, indicating that the DA and 5-HT pallidal hyperinnervations seen in MPTP monkeys result from axon sprouting rather than from the appearance of newly formed axon varicosities on non-growing axons. At the ultrastructural level, pallidal TH+ and SERT+ axons were morphologically similar in MPTP and controls, and their synaptic incidence was very low suggesting a volumic mode of transmission. Altogether, our data reveal a significant sprouting of DA and 5-HT pallidal afferents in parkinsonian monkeys, the functional significance of which remains to be determined. We suggest that the marked DA hyperinnervation of the GPi represents a neuroadaptive change designed to normalize pallidal firing patterns associated with the delayed appearance of motor symptoms, whereas the 5-HT hyperinnervation might be involved in the early expression of non-motor symptoms in Parkinson's disease.
Highlights
The main neuropathological hallmark of Parkinson’s disease (PD) is a progressive degeneration of dopamine (DA) neurons located in the substantia nigra pars compacta (SNc) leading to a massive loss of DA input to the striatum
All experimental procedures were approved by the Abbreviations: 5-HT, Serotonin; a, Axon; A, Anterior; av, Axon varicosity; CB, Calbindin; cp, Cerebral peduncle; db, Dendritic branch; dopamine beta-hydroxylase (DBH), Dopamine beta-hydroxylase; DA, Dopamine; DAB, 3,3′ diaminobenzidine tetrahydrochloride; DA transporter (DAT), Dopamine transporter; glial-cell-line-derived neurotrophic factor (GDNF), Glial-cell-line-derived neurotrophic factor; GPe, External segment of the globus pallidus; GPi, Internal segment of the globus pallidus; H2, Lenticular fasciculus; ic, Internal capsule; L-Dopa, L-3,4dihydroxy-phenylalanine, ; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; P, Posterior; PBS, Sodium phosphate-buffered saline; PD, Parkinson’s disease; positron emitting tomography (PET), Positron emission tomography; PFA, Paraformaldehyde; Put, Putamen; SERT, Serotonin transporter; SN, Substantia nigra; SNc, Substantia nigra pars compacta; STN, Subthalamic nucleus; tyrosine hydroxylase (TH), Tyrosine hydroxylase; tryptophan hydroxylase (TpH), Tryptophan hydroxylase; VTA, Ventral tegmental area
The number of TH+ neurons in the SNc of MPTP monkeys is decreased by 70.5–82.5% (Figure 1; see Gagnon et al, 2016), leading to a 84.0–89.4% decline of TH and to a 82.4–90.0% diminution of DAT immunoreactivity in the sensorimotor functional territory of the striatum (Table 1)
Summary
The main neuropathological hallmark of Parkinson’s disease (PD) is a progressive degeneration of dopamine (DA) neurons located in the substantia nigra pars compacta (SNc) leading to a massive loss of DA input to the striatum. There is a growing interest in the fate of 5-hydroxytryptamine (serotonin or 5-HT) neurons in PD, mainly because of evidence that 5-HT striatal afferents are the main presynaptic determinant in the expression of L-3,4dihydroxy-phenylalanine (L-Dopa)-induced dyskinesia (Carta et al, 2007), a motor disability characterized by abnormal involuntary movements that affect more than 75% of PD patients after only 15 years of dopatherapy (Yahr, 1972; Obeso et al, 2000; Rajput et al, 2002; Hely et al, 2005). In the hope to shed a new light on the role of pallidal DA and 5-HT innervations in PD pathogenesis, we designed a study to determine the state of DA and 5-HT axonal projections to the internal (GPi) and external (GPe) segments of the pallidum in cynomolgus monkeys rendered parkinsonian after MPTP intoxication
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