gms | German Medical Science

Objective: Ventral mesencephalic (VM) grafts of E14 rat embryos, implanted into the lesioned striatum (STR) in the unilateral 6-hydroxydopamine (6-OHDA) adult rat model of Parkinson's disease (PD), can partially restore dopamine (DA) neurotransmission in the transplanted area and improve motor deficits. The main reason of this ectopic graft placement is the inability of VM grafts transplanted into the substantia nigra (SN) to outgrow fibres to reach and reinnervate the lesion STR in the adult 6-OHDA rat model. In contrast, in the neonatal rat model graft-derived axonal outgrowth can be observed until postnatal day (P) 10 when E14 VM-derived cells are transplanted into the lesioned SN. This study investigates the impact of the host's age on axonal outgrowth of transplanted VM foetal cells implanted to the SN in the neonatal 6-OHDA rat model of PD.

Methods: Neonatal rats were bilaterally lesioned by intraventricular injections of 6-OHDA on P1 and received E14 VM grafts on P10, P11, P12, P13, P15, and P18 into the right SN. Rotational behaviour was assessed until three months after the surgery. Stereotactic injections of the retrograde tracer FluroGold in the right STR for tracing newly formed connections between the SN and the STR were performed and grafts were evaluated by immunohistochemistry and stereology.

Results: Animals that had received a graft on P10, P11, and P12 showed a significant rotational bias (p<0.05) induced by apomorphine injection compared to all other groups. Amphetamine-induced rotation revealed no difference between the experimental groups. However, animals transplanted on P10 and P11 displayed a strong rotational behaviour. Morphological and stereological analyses of the grafts revealed a similar cell distribution and integration pattern in all groups. Fibre outgrowth from SN to STR was only observed on the P10 group. In addition, DA cell survival on P10 was 3-times higher compared to all other groups. FluoroGold retrograde tracer experiments showed a high number of TH-positive cells that co-expressed FluroGold in the P10 group.

Conclusions: The benefit of grafting concerning fibre outgrowth and behavioural performance depends on the host age and was best when transplantation was performed on P10. Thus, the potential of E14 VM grafts in the SN to extend axons to the STR is determined by the developmental cues expressed during the early postnatal age. The results may also further the development of neurorestorative strategies and promote a better integration and long distance connectivity of transplanted neurons in PD patients.