Abstract
The chronic use of L-Dopa for alleviating the motor symptoms of Parkinson’s disease often produces adverse effects such as dyskinesia. Unregulated release of dopamine by serotonin axons following L-Dopa administration is a major presynaptic determinant of these abnormal involuntary movements. The present study was designed to characterize the reorganization of serotonin striatal afferents following dopaminergic denervation in a primate model of Parkinson’s disease. Our sample comprised eight cynomolgus monkeys: four that were rendered parkinsonian following MPTP administration and four controls. The state of striatal serotonin and dopamine innervation was evaluated by means of immunohistochemistry with antibodies against serotonin transporter (SERT) and tyrosine hydroxylase. A detailed stereological investigation revealed a significant increase in the number of serotonin axon varicosities in the striatum of MPTP-intoxicated monkeys. This increase is particularly pronounced in the sensorimotor territory of the striatum, where the dopamine denervation is the most severe. Electron microscopic examinations indicate that, in contrast to the nucleus accumbens where the dopamine innervation is preserved, the SERT+ axon varicosities observed in the sensorimotor territory of the putamen establish twice as many synaptic contacts in MPTP-intoxicated monkeys than in controls. These findings demonstrate the highly plastic nature of the serotonin striatal afferent projections, a feature that becomes particularly obvious in the absence of striatal dopamine. Although the number of dorsal raphe serotonin neurons remains constant in parkinsonian monkeys, as shown in the present study, their ascending axonal projections undergo marked proliferative and synaptic adaptive changes that might play a significant role in the potential unregulated and ectopic release of dopamine by serotonin axons after L-Dopa treatment of Parkinson’s disease.
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Abbreviations
- 4:
-
Trochlear nucleus
- 5-HT:
-
Serotonin, 5-hydroxytryptamine
- AADC:
-
Aromatic L-amino acid decarboxylase
- ac:
-
Anterior commissure
- Acb:
-
Nucleus accumbens
- Aq:
-
Cerebral aqueduct
- Cd:
-
Caudate nucleus
- DA:
-
Dopamine
- DAB:
-
3,3′ diaminobenzidine tetrahydrochloride
- DAT:
-
Dopamine transporter
- db:
-
Dendritic branch
- DRN:
-
Dorsal raphe nucleus
- ic:
-
Internal capsule
- L-Dopa:
-
L-3,4-dihydroxy-phenylalanine
- LIDs:
-
L-Dopa-induced dyskinesia
- MPTP:
-
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- MRN:
-
Median raphe nucleus
- PB:
-
Sodium phosphate buffer
- PBS:
-
Sodium phosphate-buffered saline
- PAG:
-
Periaqueducal gray
- PET:
-
Positron emission tomography
- PFA:
-
Paraformaldehyde
- Put:
-
Putamen
- RT:
-
Room temperature
- SC:
-
Superior colliculus
- SERT:
-
Serotonin transporter
- SNc:
-
Substantia nigra pars compacta
- TBS:
-
Tris-saline buffer
- TH:
-
Tyrosine hydroxylase
- TpH:
-
Tryptophan hydroxylase
- VMAT2:
-
Vesicular monoamine transporter 2
- xscp:
-
Decussation of superior cerebellar peduncle
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Acknowledgments
This study was supported by research grant from the Canadian Institutes of Health Research (CIHR MOP-115008). MP received a career award from the “Fonds de Recherche du Québec, Santé (FRQS)”. DG was the recipient of a PhD fellowship from FRQ-S. The authors are grateful to Marie-Josée Wallman, Caroline Côté and Marc Morissette for technical assistance. The authors have no conflict of interest to declare.
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Online resource 1 Information on control and MPTP-intoxicated monkeys used in this study. Abbreviations: NA: Not applicable (PDF 63 kb)
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Online resource 2 Immunoreactivity for the dopamine transporter (DAT) in the striatum of control and MPTP-intoxicated monkeys. (A) Schematic representations of the striatal functional territories, at three anteroposterior levels, each identified with its own color (see Fig. 2 legend for further details). (B, C) Histograms of optical density measurements of DAT immunoreactivity in the sensorimotor (B), the associative and the limbic (C) striatal territories, at the three anteroposterior levels examined. Optical density measurements indicate a significant decrease of DAT immunoreactivity throughout the striatum, except in the limbic striatal territory. * P < 0.05 using Mann-Whitney U test (PDF 315 kb)
429_2015_1125_MOESM3_ESM.pdf
Online resource 3 Number of SERT immunoreactive axon varicosities per 10 µm of axon in the various functional territories of the striatum, in controls and MPTP-intoxicated monkeys. (A) Schematic representations of the striatal functional territories, at the three anteroposterior levels, each identified with its own color (see Fig. 2 legend for further details). (B, C) Histograms showing the number of SERT+ axon varicosities per 10 µm of axons in the sensorimotor (B), the associative and limbic (C) striatal territories, at the three anteroposterior levels examined. No significant differences were observed between MPTP and control animals, suggesting that the sprouting of SERT+ varicose axons causes the increase in the density of SERT+ axon varicosities (PDF 298 kb)
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Gagnon, D., Gregoire, L., Di Paolo, T. et al. Serotonin hyperinnervation of the striatum with high synaptic incidence in parkinsonian monkeys. Brain Struct Funct 221, 3675–3691 (2016). https://doi.org/10.1007/s00429-015-1125-5
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DOI: https://doi.org/10.1007/s00429-015-1125-5