Diminished Viability, Growth, and Behavioral Efficacy of Fetal Dopamine Neuron Grafts in Aging Rats with Long-Term Dopamine Depletion: An Argument for Neurotrophic Supplementation

Abstract

We examined the behavioral and morphological correlates of the response to a single intrastriatal dispersed cell graft of fetal rat ventral mesencephalic tissue in male Fischer-344 rats of varying age (4, 17, and 24–26 months old) and history of mesostriatal dopamine (DA) depletion (1 or 14 months). Our goal was to determine the impact of advancing age and duration of DA depletion in the host on DA graft viability and function. The findings can be summarized as follows. (1) Fetal DA neuron grafts that were effective in completely ameliorating amphetamine-induced rotational behavior in young rats with short-term lesions were virtually without effect in aged rats with long-term lesions. Middle-aged rats with long-term lesions responded to these grafts with partial behavioral recovery. (2) Age of the host at the time of transplantation, and not duration of DA depletion, was the primary determinant of response to DA grafts. (3) Diminished efficacy of grafts in lesioned aging rats was related to decreased survival and neurite extension of transplanted DA neurons. (4) Co-grafts of DA neurons with Schwann cells as a source of neurotrophic support improved the behavioral outcome of grafts in aged lesioned rats. These findings support the view that the DA-depleted striatum of aged rats is an impoverished environment for survival, growth, and function of DA grafts. Consistent with this view, local supplementation of the neurotrophic environment of grafted DA neurons with products of co-grafted Schwann cells, a demonstrated source of neurotrophic activity for embryonic DA neurons, improved graft outcome.