Reformation of the nigrostriatal pathway by fetal dopaminergic micrograftsinto the substantia nigra is critically dependent on the age of the host

The aim of this study was to determine whether the growth of axons along th e nigrostriatal pathway from fetal dopamine cells, transplanted into the su bstantia nigra of young postnatal 6-OHDA-lesioned rats, is dependent on the age of the host brain, Neonatal rats were lesioned bilaterally by intraven tricular injection of 6-OHDA at postnatal day 1 (P1) and received grafts of E14 ventral mesencephalon at day 3 (group P3), day 10 (group P10), or day 20 (group P20) into the right substantia nigra. One lesioned group was left untransplanted. Six months after surgery the animals were subjected to ana lysis of drug-induced rotation following injection of amphetamine, apomorph ine, a DI agonist (SKF38393), or a D2 agonist (Quinpirole). Animals transpl anted intranigrally at day 3 and day 10 showed a strong amphetamine-induced rotational bias toward the side contralateral to the transplant. Animals t ransplanted into substantia nigra at P20, like the lesioned control animals , showed no rotational bias. Apomorphine and selective D1 and D2 agonists i nduced ipsilateral turning behavior in the P3 and P10 group, but not in the P20 or the lesion control groups. Immunoflorescence histochemistry in comb ination with retrograde axonal tracing, using FluoroGold injection into the ipsilateral caudate-putamen showed colocalization of tyrosine hydroxylase and FluoroGold in large numbers of transplanted neurons in the animals tran splanted at postnatal day 3 and postnatal day 10, which was not observed in the group P20. The lesion control group showed a 90% complete lesion of th e TH-positive cells in the substantia nigra while largely sparing the neuro ns in the ventral tegmental area. The results indicate that intranigral gra fts can be placed accurately and survive well within the substantia nigra r egion at various time points during postnatal development. Furthermore, emb ryonic dopamine neurons have the ability to extend axons along the nigrostr iatal pathway and reconnect with the dopamine-depleted striatum when transp lanted at postnatal day 3 and postnatal day 10, but not at postnatal day 20 . (C) 1999 Academic Press.