Effects of Donor Age and Brain-Derived Neurotrophic Factor on the Survival of Dopaminergic Neurons and Axonal Growth in Postnatal Rat Nigrostriatal Cocultures

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Early postnatal rat brain tissue can be grown for several weeks as organotypic slice cultures by the roller-tube method. We have here used this method to study the effects of donor age and brain-derived neurotrophic 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 prepared from newborn and 7-day-old rats and cocultured for 3--3 1/2 weeks with different combinations of the two donor ages. After immunocytochemical staining the number of TH-i, ventral mesencephalic neurons were counted, and the growth of TH-i fibers into the striatal part of the cocultures was evaluated. Co-cultures, with both VM and striatal slices prepared from newborn rats, contained a significantly higher number of TH-i neurons and displayed a significantly increased innervation of the striatal slices compared with other combinations of donor ages. Addition of BDNF resulted in both an increased survival of TH-i neurons and an increased growth of TH-i fibers into the cocultured striatal slices. Significant neurotrophic effect of BDNF did, however, require young donor age of both VM and striatal slices. It is suggested that BDNF induces more cells, possibly progenitor cells, to express TH immunoreactivity. Alternatively BDNF may suppress apoptotic cell death documented by others to occur in the postnatal rat substantia nigra pars compacta. Irrespective of the mechanisms, survival of more TH-i neurons was related to an increased innervation of the striatal slices by TH-i nerve fibers. The observed effects of BDNF on both survival and fiber growth of TH-i neurons indicate a potential role of BDNF for treatment of Parkinson's disease or grafts of immature DA neurons transplanted to patients with Parkinson's disease. A significant trophic effect of BDNF did, however, seem to depend on young developmental age of both striatum and VM. Parallel treatment with striatal neurotrophic factors may therefore be a necessary prerequisite to a trophic effect of BDNF under clinical conditions.