The differentiation of dopaminergic neurons in situ, in vivo, and in transplants

This article summarizes results obtained from studies on the differentiation of dopaminergic neurons in animal hypothalamus and human substantia nigra in situ, in vitro, and in transplants, as well as the role of the microenvironment in regulating this process. Four stages were identified in the differentiation of dopaminergic neurons from rat hypothalamus: a) formation of neurons from neuroepithelial precursor cells, b) expression of specific synthetic products (enzymes and dopamine itself) and mechanisms for transmembrane dopamine transport (reuptake and secretion in response to membrane depolarization), c) formation of permanent and transient efferent connections, and d) formation of afferent innervation and synaptogenesis. Along with dopaminergic neurons, rat fetuses contained neurons expressing only one of the dopamine-synthesizing enzymes and probably taking part in in situ dopamine synthesis. Differentiation of dopaminergic neurons was sexually dimorphic in terms of the dynamics of neuron formation and expression of enzymes involved in dopamine synthesis. A neurotransplantation model showed that humoral factors of placental and maternal origin had no significant effect on the differentiation of the dopaminergic neurons of the hypothalamus. As regards the dopaminergic neurons of the substantia nigra, expression of their specific phenotype in human fetuses started with the synthesis of tyrosine hydroxylase and co-maturation of the specific dopamine reuptake mechanism during the sixth week of development. During the next four weeks, specific uptake increased, and this appears to be a measure of the number of neurons and the growth of their processes. These data provide the basis for regarding the period from week 6 to week 10 as optimal for transplantation of dopaminergic neurons into the striatum of patients with Parkinson's disease. Suspensions of fetal substantia nigra cells enriched with dopaminergic neurons were introduced stereotaxically into a patient's striatum through a cannula. Positron emission tomography studies showed that the transplanted neurons survived within the host brain, underwent differentiation, and started to synthesize dopamine. The results of clinical assessment performed in parallel with these studies suggested that the transplanted dopaminergic neurons were involved in regulating striatal target neurons.