BRAIN-DERIVED NEUROTROPHIC FACTOR ENHANCES FUNCTION RATHER THAN SURVIVAL OF INTRASTRIATAL DOPAMINE CELL-RICH GRAFTS

Brain-derived neurotrophic factor (BDNF) has been shown to promote the survival of dopaminergic neurons from the substantia nigra in cell culture. In order to assess whether a similar survival-promoting effect is present also in vivo, we grafted fetal nigral tissue to the dopamine-depleted striatum of 6-hydroxydopamine-lesioned rats receiving two-week intraventricular infusions or daily intrastriatal injections of BDNF, NGF, or vehicle. When infused chronically at a high dose (12 mug/day) into the lateral ventricle, BDNF caused a behavioral syndrome of reduced food and water intake, body weight loss, and locomotor hyperactivity in comparison to NGF- and vehicle-infused graft recipients. NGF-infused graft recipients displayed a transient weight loss during the first week of infusion. At 15 days, amphetamine-induced turning was significantly attenuated to 3% of pregraft values in BDNF-infused recipients, whereas functional graft effects were not present in NGF- or vehicle-infused animals. Survival of tyrosine hydroxylase-immunoreactive graft cells, however, was similar in all treatment groups. Notably, NGF- and BDNF-infusions led to a significant size increase of cholinergic host neurons in the medial septal nucleus and the vertical limb of the diagonal band ipsilateral to the infusion, wheras there was no cholinergic neuron hypertophy in vehicle-infused animals. Daily intrastriatal injections of BDNF (2 mug) produced no weight loss or locomotor hyperactivity, but also enhanced functional graft effects in BDNF-injected, as compared to vehicle-injected animals. Survival rates of grafted tyrosine hydroxylase-immunoreactive cells were, however, similar in both groups. We conclude that, using the administration methods chosen for this study, BDNF may enhance the functional capacity but not the survival of grafted dopamine neurons.