EFFECTS OF DONOR AGE AND BRAIN-DERIVED NEUROTROPHIC FACTOR ON THE SURVIVAL OF DOPAMINERGIC-NEURONS AND AXONAL GROWTH IN POSTNATAL RAT NIGROSTRIATAL COCULTURES

Early postnatal rat brain tissue can be grown for several weeks as org anotypic slice cultures by the roller-tube method. We have here used t his method to study the effects of donor age and brain-derived neurotr ophic factor (BDNF) on the survival and growth of tyrosine hydroxylase immunoreactive (TH-i), dopaminergic (DA) neurons during the postnatal period when their nerve fibers normally innervate the striatal target . Tissue slices of ventral mesencephalon (VM) and striatum were prepar ed from newborn and 7-day-old rats and cocultured for 3-3 1/2 weeks wi th different combinations of the two donor ages. After immunocytochemi cal staining the number of TH-i, ventral mesencephalic neurons were co unted, and the growth of TH-i fibers into the striatal part of the coc ultures was evaluated. Co-cultures, with both VM and striatal slices p repared from newborn rats, contained a significantly higher number of TH-i neurons and displayed a significantly increased innervation of th e striatal slices compared with other combinations of donor ages. Addi tion of BDNF resulted in both an increased survival of TH-i neurons an d an increased growth of TH-i fibers into the cocultured striatal slic es. Significant neurotrophic effect of BDNF did, however, require youn g donor age of both VM and striatal slices. It is suggested that BDNF induces more cells, possibly progenitor cells, to express TH immunorea ctivity. Alternatively BDNF may suppress apoptotic cell death document ed by others to occur in the postnatal rat substantia nigra pars compa cta. Irrespective of the mechanisms, survival of more TH-i neurons was related to an increased innervation of the striatal slices by TH-i ne rve fibers. The observed effects of BDNF on both survival and fiber gr owth of TH-i neurons indicate a potential role of BDNF for treatment o f Parkinson's disease or grafts of immature DA neurons transplanted to patients with Parkinson's disease. A significant trophic effect of BD NF did, however, seem to depend on young developmental age of both str iatum and VM. Parallel treatment with striatal neurotrophic factors ma y therefore be a necessary prerequisite to a trophic effect of BDNF un der clinical conditions. (C) 1996 Academic Press, Inc.