OPTIMAL EFFECTIVENESS OF BDNF FOR FETAL NIGRAL TRANSPLANTS COINCIDES WITH THE ONTOGENIC APPEARANCE OF BDNF IN THE STRIATUM

Transplantation of fetal nigral dopamine neurons into the caudate and putamen of Parkinson's disease patients produces limited symptomatic r elief. One approach to augment the outgrowth and function of nigral gr afts includes exposure of the graphs to neurotrophic factors; however, the temporal requirements for optimizing these actions are unknown. T he present study characterized the ontogeny of brain-derived neurotrop hic factor (BDNF) in the rat striatum and used this information to def ine and evaluate three distinct periods of BDNF infusion into fetal ni gral grafts transplanted into the striatum of rats with experimental P arkinson's disease. At postnatal day 1 (P1), BDNF and dopamine were me asured at 17 and 27% of peak levels, respectively that occurred at P27 for both. Both compounds showed their greatest surge between P7 and P 20, increasing from 40% to similar to 95% of peak levels. Exogenous BD NF infused into transplants during weeks 1 and 2 after the transplanta tion, which coincide with the developmental period embryonic day 14 (E 14)-P7 for transplanted tissue, did not improve rotational behavior or enhance fiber outgrowth of transplanted dopamine neurons. Delaying th e BDNF infusion until transplanted tissue was approximately P8-P21 gre atly enhanced the effect on rotational behavior and doubled the area o f dopamine fiber outgrowth from the transplants. Delaying the infusion until transplanted tissue was approximately P36-P49 failed to augment fiber outgrowth and decreased the behavioral function of transplants. Thus, the optimal effect of exogenous BDNF on the development of dopa mine neurons in fetal nigral transplants occurs at a postnatal age whe n endogenous dopamine and BDNF show the greatest increases during the normal development of the striatum.