Differential response of ventral midbrain and striatal progenitor cells tolesions of the nigrostriatal dopaminergic projection

In response to injury, progenitor cells in the adult brain can proliferate and generate new neurons and/or glia, which may then participate in injury- induced compensatory processes. In this study, we explore the ability of yo ung adult mice to generate new cells in response to 1-methyl-4-phenyl-1,2,3 ,6-tetrahydropyridine (MPTP) lesions, which selectively kill nigrostriatal dopaminergic neurons. Using the thymidine analogue 5-bromo-2'-deoxyuridine (BrdU), we labeled dividing cells 3, 10, and 15 days after MPTP lesion. A r obust proliferative response was seen specifically in the substantia nigra (SN) and the dorsal striatum 3 days postlesion; the response persisted 10-1 4 days. To explore the fate of proliferative cells, we administered BrdU 3 days postlesion and examined the phenotype of BrdU(+) cells at various time s thereafter, using double immunolabeling. In the striatum, nearly all newl y-generated cells rapidly differentiated into GFAP(+) astrocytes that parti cipated in the injury-induced glial reaction. In the SN, however, reactive astroglia were not BrdU(+). Some midbrain cells co-immunostained for BrdU a nd Mac-1, a microglial marker. However, most BrdU(+) cells in the SN failed to express markers for microglia, astroglia, oligodendroglia, or neurons, suggesting that they may remain as uncommitted progenitors. Thus, progenito rs in the vicinity of the degenerating dopaminergic cell bodies respond dif ferently to lesion than progenitors in the vicinity of the degenerating axo n terminal. Although the putative midbrain progenitors appear uncommitted 2 2 days after their birth, it is possible that they may adopt neural or glia l fates if allowed to survive longer, or if exposed to exogenous factors. C opyright (C) 2000 S. Karger AG. Basel.