Brain Advance Access originally published online on February 15, 2006
Brain 2006 129(5):1194-1200; doi:10.1093/brain/awl041
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New striatal dopamine neurons in MPTP-treated macaques result from a phenotypic shift and not neurogenesis
1 INSERM U679, Neurology and Experimental Therapeutics, 2 Salpetriere Hospital, 3 Pierre and Marie Curie University, Faculty of Medicine, Paris, France and 4 Department of Neurology, Experimental Neurology Unit, Philipps University, Marburg, Germany
Correspondence to: Chantal François, INSERM U679, Laboratoire de Neurologie et Thérapeutique Expérimentale, Hôpital de la Salpêtrière, 47 Boulevard de l'Hôpital, 75651, Paris, cedex 13, France E-mail: cfrancoi{at}ccr.jussieu.fr
We investigated whether there is neurogenesis in the striatum of aged monkeys, and whether dopamine (DA) depletion induces the genesis of new DA neurons in this structure. Six aged macaques received repeated intraperitoneal injections of bromodeoxyuridine (BrdU) over a 3 week period to label dividing cells. Three macaques were injected in parallel with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to decrease dopaminergic innervation of the striatum. The brains were analysed 3 weeks after the last BrdU injection. In MPTP-treated aged macaques, the number of tyrosine hydroxylase (TH) immunoreactive (ir) striatal neurons increased 2.3-fold compared with controls. These TH-ir striatal cells did not express dopamine beta hydroxylase (DBH) but the dopamine transporter (DAT), suggesting that they are functional DA neurons. They were also negative for calbindin (CB), neuropeptide Y (NPY) and parvalbumin (PV), and a small proportion expressed calretinin (CR). This suggests that these cells stained for TH are interneurons. All these cells also co-expressed glutamic acid decarboxylase (GAD). They thus resemble the small, aspiny, GABAergic interneurons. None of the BrdU-labelled cells in the striatum expressed the neuronal markers neuronal nuclei (NeuN), or GAD or TH, and none of TH-ir cells incorporated BrdU. These data indicate that neurogenesis did not occur in the striatum of aged macaques. The new striatal TH-ir neurons observed after DA depletion was therefore derived from pre-existing GABAergic interneurons. Understanding of the molecular signals mediating this phenotypic shift might help in developing novel and elegant strategies for a cell-based therapy for Parkinson's disease that would avoid many of the drawbacks of cell transplantation.
Key Words: primates; Parkinson's disease; neurogenesis; advancing age
Abbreviations: BrdU = bromodeoxyuridine; CB = calbindin; DA = dopamine; DAPI = 4',6'-diamidino-2-phenylindole-dihydrochloride; DAT = dopamine transporter; DBH = dopamine beta hydroxylase; GAD = glutamic acid decarboxylase; ir = immunoreactive; MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NeuN = neuronal nuclei; NPY = neuropeptide Y; PBS = phosphate-buffered saline; PV = parvalbumin; TH = tyrosine hydroxylase
Received November 8, 2005. Revised January 13, 2006. Accepted January 24, 2006.
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