Profound astrogenesis in the striatum of adult mice following nigrostriatal dopaminergic lesion by repeated MPTP administration

Neural progenitor cells are present in the rodent brain throughout adulthoo d, and can proliferate and differentiate into new neurons and/or glia to re pair injury. To explore the repair processes mediated by brain progenitor c ells, a selective lesion of the nigrostriatal dopaminergic pathway was indu ced in young adult mice by repeated administration of the neurotoxin, 1-met hyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). A thymidine analog, bromode oxyuridine (BrdU), was used as a tracer for DNA synthesis to label the divi ding cells and their terminal progeny following injury. Three days after MP TP treatments (25 mg/kg, once daily for 5 days), an 8-fold increase in the number of BrdU-labeled newborn cells was observed in the dorsal striatum. A 5-fold increase was also seen in the substantia nigra (SN). Newborn cells in the striatum survived beyond 60 days after their birth whereas newborn c ells in the SN survived for less than 31 days. The vast majority of newborn cells in the striatum differentiated into astroglia according to their rad ial morphology and co-expression with an astroglial marker, S100 beta, with in 10 days after birth. In contrast, most BrdU-positive cells in the SN fai led to co-express S100 beta. Little or none of BrdU-labeled cells in both t he striatum and SN were found to co-localize with a neuronal marker, neuron al nuclear antigen, or tyrosine hydroxylase during the full course of survi val days surveyed (3 to 60 days). Repeated MPTP also decreased dopamine con tent and uptake in the striatum, which showed a significant recovery 31 day s after MPTP lesion. These results demonstrate a rapid and profound astroge nesis in the striatum of young adult mice in response to toxic dopaminergic insult. The lack of neurogenesis in the two affected brain areas indicates the relative importance of glial cell regeneration in repairing MPTP injur y. (C) 2001 Elsevier Science B.V. All rights reserved.