Neurochem. Int. Vol. 20, Suppl.,pp. 309S-320S,1992 0197-0186/92 $5.00+0.00 Printedin Great Britain.All fightsreserved Copyright© 1992Pergamon Presspie EMBRYONIC DOPAMINERGIC NEURON TRANSPLANTS IN MPTP LESIONED MOUSE STRIATUM UMBERTO DI PORZIO l a n d ALESSANDRO ZUDDAS 2 qstltuto Internazionale di Genetica e Biofisica, CNR, Naples, and Istituto di Farma~logia, Scuola Medica, Universit~ di Pisa, Italy ~Laboratory of Neurophysioiogy and Clinical Neuroscience Branch, NINDS, National Institutes of Health, Bethesda, MD 20892, U.S.A. Almraet-- The aim of this work is to study CNS development and plasticity, and to study the mechanisms that allow exogenous embryonic dopaminergic neurons to restore transmitter function in the experimental parkinsonism. Recently, we have developed a new method that produces a selective degeneration of the dopaminergic nigrostriatal system in mice by a combined acetaldehyde/MPTP treatment. This procedure results in a selective and irreversible loss of substantia nigra dopaminergic neurons in C57BL mice, while other dopaminergic areas of the brain are spared. MPTP alone results instead only in a temporary, reversible damage of nigro- striatai dopaminergic functions. Embryonic dopaminergic neurons from ventral mesencephalon or hypothalamus are implanted in lesioned or normal right striata or lateral ventricles. The mesencephalic neurons implanted in a lesioned host form a dense network of fibers which establish functional reinnervation of the striatum (or caudate-putamen complex). After several months about the entire striatal parenchyma appears reinnervated; on average, 20% of the grafted mesencephalic dopaminergic cells survive. Implants of embryonic HYP neurons instead, show little or no survival. Moreover, dopaminergic mesencephalic neurons in control non-lesioned animals show apoor development with little fiber outgrowth. These data indicate that interactions between embryonic dopanfincrgic neurons and ndult striatal neurons is specific. They also suggest that this specificity is sustained by trophic and/or tropic factors ~bly produced by the lesioned striatum and by putative inhibitory mechanisms of cell migration and neuritic outgrowth. In the last few years several studies have shown that transplants of foetal neurons can promote functional recovery of damaged neuronal circuits. Thus grafting has received considerable interest as a possible thera- peutic approach to degenerative disorders of the Central Nervous System (CNS) (Bj6rklund and Stenevi, 1985; Yurek and Sladek, 1990). To date several patients suffering from Parkinson's disease (PD) have been treated either with autologous adrenal medulla (Madrazo et al., 1987) or foetal mesen- cephalic (MES) cells (Hitchcock et al., 1990) to replace the degenerated dopaminergic (DA) neurons in the nigrostriatal pathway. Transplants of adrenal medulla in several animal models of nigro-striatal lesion have indicated that chromatfm cells induce sprouting of DA fibres, although they survive only for a limited time (Bohn et al., 1987; Bankiewicz et al., 1990). A similar recovery was induced by basic Fibroblast Growth Factor in the nigro-striatal system of MPTP-troated mice (Otto and Unsicker, 1990), although it remains to be established whether bFGF has any direct effect. Despite the large number grafts of catecholamine cell conducted so far, the biology of transplanted DA cells and the reorganization of their circuitry still remains to be elucidated. On the other hand, implanted brain tissues can help us to explore CNS development and plasticity. Bilateral destruction of the dopaminergic nigro- striatal neurons produces in mammals a well, characterized syndrome reflecting impaired motor function and sensory motor integration (for review see Zigmond et al., 1987). Primates treated with 1-methyl- 4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), a selective toxin for the nigrostriatal pathway, develop experimental parkinsonism (Bums et al., 1986). While rats are almost insensitive to MPTP toxicity, mice treated with high doses of MPTP show a temporary reduction of dopamine (DA) and its metabolites in the striatum (str, CuP), with limited loss of DA neurons in the substantia nigra pars compacta (SNc, Ag) (Heikkila et al., 1984, Hallman et al., 1985, Ricaurte et al., 1986). Recently, we have developed a method that produces a permanent bilateral lesion of the nigrostriatal pathway in C57BL mice (Zuddas et al., 1989a, 1989b). The treatment, consisting in injections of MPTP and ethanol or acetaldehyde (ACE), causes an extensive and selective cell death in the SNc sparing DA neurons in the ventral tegmental area (VTA; Ai0). Several months after treatment there is no recovery of 309S