Development of A9/A10 dopamine neurons during the second and third trimesters in the African green monkey

Disruption in the development of dopamine-containing neurons has been postulated to underlie several CNS disorders. However, there have been no quantitative studies on the normal development of primate dopamine neurons. Thus, the fetal maturation of primate midbrain dopamine neurons was examined to establish changes that occur in the A9/A10 groups during the second and third trimesters. Eleven fetal African green monkey midbrains were immunostained for tyrosine hydroxylase (TH-ir) as a marker for dopamine neurons and quantified using stereological techniques (nucleator method). The number and size of defined dopamine neurons and the volume occupied by A9/A10 neurons increased in near linear fashion throughout the term. The estimated number of defined dopamine neurons in each hemisphere rose from approximately 50,000 at embryonic day (E) 70 to 225,000 at birth (E165), similar to the adult population. The size and the area occupied by them at birth were, however, well below the estimated adult levels. Additionally, the younger fetal midbrains had far less diversity in dopamine cell volumes compared with older fetuses and adult brains. Until midway through gestation (E81), clusters of apparently immature midbrain TH-ir cells were observed, but could not be counted. Even though the majority of cells destined to become dopamine neurons are generated in the first trimester, phenotypical maturation of A9 and A10 cell bodies continues steadily throughout gestation and extends well into the postnatal period. These data have relevance to transplantation studies that employ fetal dopaminergic grafts, and to disorders hypothesized to result from damage to developing midbrain dopamine neurons.