Development of intracerebral dopaminergic grafts: a combined immunohistochemical and autoradiographic study of its time course and environmental influences.

The aim of the study was to obtain a description of some aspects of the development of intracerebral dopaminergic grafts, namely, the time course of the glial reaction and its relation to cell division on one hand, and the development of graft-originated innervation and its dependence on adequate matching of the implanted neurons and target site on the other hand. Cell suspensions obtained from the mesencephalon or hypothalamus of embryonic day (ED) 14 rat embryos were implanted into the striatum or lateral hypothalamus of adult rats following the destruction of the nigrostriatal system of the hosts. Animals were sacrificed at different postimplantation times, and the development of the graft was followed by immunohistochemistry by using antisera directed against tyrosine hydroxylase (TH) or glial fibrillary acidic protein (GFA). Furthermore, the existence of cell division at various times following implantation was examined by performing autoradiography on immunostained sections after prior intraventricular administration of 3H-thymidine to the host. The first stage of the development of intracerebral grafts was characterized by the existence of intense cell division within the grafted tissue, lasting about 2 weeks, and also in the host tissue surrounding the graft, lasting only about 6 days. The cell division in the host tissue was paralleled by the existence of a strong glial reaction which, however, did not extend into the graft itself. Glial reaction in the host tissue gradually decreased at later times and disappeared by 4 weeks postimplantation without leaving behind a noticeable glial scar. The graft itself was, however, transiently filled with a population of reactive astroglial cells between 3 and 6 weeks postimplantation. Within grafts of mesencephalic tissue located in the striatum TH-positive neurons were distributed evenly at short times postimplantation (2-6 days). At later time a compartmentation could be observed, with TH-positive neurons being aligned along the graft-host interface or clustered within the graft itself. Innervation of the host tissue by TH-positive fibers increased between 1 and 6 weeks postimplantation. On the other hand, no compartmentation and reinnervation of surrounding host tissue was observed for intrahypothalamic grafts of mesencephalic tissue or intrastriatal grafts of hypothalamic tissue. This last observation indicates that adequate matching of implanted neurons and target tissue plays an important role in the development of intracerebral dopaminergic grafts.