FUNCTIONAL FETAL NIGRAL GRAFTS IN A PATIENT WITH PARKINSONS-DISEASE -CHEMOANATOMIC, ULTRASTRUCTURAL, AND METABOLIC STUDIES

A patient with Parkinson's disease received bilateral fetal human nigr al implants from six donors aged 6.5 to 9 weeks post-conception. Eight een months following a post-operative clinical course characterized by marked improvement in clinical function, this patient died from event s unrelated to the grafting procedure. Post-mortem histological analys es revealed the presence of viable grafts in all 12 implant sites, eac h containing a heterogeneous population of neurons and glia. Approxima tely 210,146 implanted tyrosine hydroxylase-immunoreactive (TH-ir) neu rons were found. A greater number of TH-ir grafted neurons were observ ed in the right (128,162) than the left (81,905) putamen. Grafted TH-i r neurons were organized in an organotypic fashion. These cells provid ed extensive TH-ir and dopamine transporter-ir innervation to the host striatum which occurred in a patch-matrix fashion. Quantitative evalu ations revealed that fetal nigral grafts reinnervated 53% and 28% of t he post-commissural putamen on the right and left side, respectively. Grafts on the left side innervated a lesser area of the striatum; but optical density measurements were similar on both sides. There was no evidence that the implants induced sprouting of host TH-ir systems. El ectron microscopic analyses revealed axo-dendritic and occasional axo- axonic synapses between graft and host. In contrast, axe-somatic synap ses were not observed. In situ hybridization for TH mRNA revealed inte nsely hybridized grafted neurons which far exceeded TH mRNA expression within residual host nigral cells. In addition, gamma-amino butyric a cid (GABA)-ergic neurons were observed within the graft that formed a dense local neuropil which was confined to the implant site. Serotoner gic neurons were not observed within the graft. Cytochrome oxidase act ivity was increased bilaterally within the grafted post-commissural pu tamen, suggesting increased metabolic activity. In this regard, a doub ling of cytochrome oxidase activity was observed within the grafted po st-commissural putamen bilaterally relative to the non-grafted anterio r putamen. The grafts were hypovascular relative to the surrounding st riatum and host substantia nigra. Blood vessels within the graft stain ed intensely for GLUT-1, suggesting that this marker of blood-brain ba rrier function is present within human nigral allografts. Taken togeth er, these data indicate that fetal nigral neurons can survive transpla ntation, functionally reinnervate the host putamen, establish synaptic contacts with host neurons, and sustain many of the morphological and functional characteristics of normal nigral neurons following graftin g into a patient with PD. (C) 1996 Wiley-Liss, Inc.