Evidence for target-specific nerve fiber outgrowth from subpopulations of grafted dopaminergic neurons: A retrograde tracing study using in oculo andintracranial grafting

Efforts have been made to counteract the symptoms of Parkinson's disease by substituting the loss of dopaminergic neurons with fetal ventral mesenceph alic grafts. One of the postulated limiting factors in this treatment is th e relatively poor cell survival and limited graft-derived fiber outgrowth. Recent results documenting enhanced survival of grafted dopaminergic neuron s showed no positive correlation to enhanced innervation of the striatal ta rget. Therefore this study was undertaken to investigate whether all surviv ing grafted dopaminergic neurons projected to the striatal target. Hence, f etal ventral mesencephalic tissue was implanted adjacent to mature versus i mmature striatal tissue using in oculo and intraventricular grafting techni ques. In in oculo grafting, fetal ventral mesencephalon was implanted simul taneously with fetal lateral ganglionic eminence (immature striatal target) or to already matured striatal in oculo grafts (mature striatal target). F urthermore, fetal ventral mesencephalon was implanted into the lateral vent ricle adjacent to mature dopamine-depleted striatum. The retrograde tracer fluorogold was injected into the striatal portion of the in oculo cografts and into reinnervated areas of the adult brain. Immunohistochemistry reveal ed that a significantly larger proportion of tyrosine hydroxylase-positive neurons in the ventral mesencephalic graft was innervating in oculo immatur e striatal tissue, and hence was fluorogold-positive, in comparison with th e number of tyrosine hydroxylase-positive neurons innervating mature striat al tissue. Moreover, intracranial transplantations showed that tyrosine hyd roxylase-positive neurons were distributed within the grafts in dense clust ers of cells. In most clusters tyrosine hydroxylase-positive cells were flu orogold-negative but calbindin-positive, In a few tyrosine hydroxylase-posi tive cell clusters, neurons were coexpressing fluorogold but were calbindin -negative, In conclusion, significantly more dopamine neurons projected to immature than to mature striatal tissue and thus, a subpopulation of grafte d dopaminergic neurons was not projecting into adult striatum. Thus, the re sults from this study show that further attempts to enhance survival of gra fted dopamine neurons in purpose to enhance graft-derived fiber outgrowth a nd efficacy should also consider different subtypes of dopamine neurons. (C ) 2001 Academic Press.