Molecular anatomy of the development of the human substantia nigra

Abstract

A series of 15 fetal and perinatal human brains (from week 12 of fetal life to day 2 after birth) was studied in order to describe the anatomical and molecular correlates of the substantia nigra ontogeny. In situ hybridization, immunohistochemistry and binding studies were used to detect D2 dopamine receptor (D2R) mRNA, D2R binding sites, dopamine membrane transporter (DAT) mRNA, tyrosine hydroxylase (TH) protein D1 dopamine receptor (D1R) protein and D1R binding sites. Dopaminergic (DA) neurons of the substantia nigra were detected through TH immunoreactivity from week 12. At week 16, the substantia nigra was clearly delineated as a compact group of intermingled neurons and fibers. From week 19, groups of DA neurons were segregated from the pars reticulata. These groups have been divided into the substantia nigra pars compacta, the ventral tegmental area and the retrorubral area. The DA neurons exhibited a gradual increase in size and branching development until birth. From week 12 onward they expressed several other markers of dopamine transmission, i.e., D2R mRNA, D2R binding sites and DAT mRNA. The ventral tegmental area expressed lower levels of mRNA for DAT and D2R than the pars compacta. From week 12, D1R immunoreactivity and D1R binding sites were also present in the substantia nigra pars reticulata. This suggests that projecting striatonigral neurons, known to express the D1R gene, have developed pathways connecting with the substantia nigra by week 12. Our results demonstrate that the developing substantia nigra in human displays early transcriptional and translational activity for the main constituents of dopaminergic transmission from week 12 and receives at this time dopaminoceptive inputs bearing D1 receptors from the striatum.

Recombinant Adeno-Associated Virus-mediated rescue of function in a mouse model of Dopamine Transporter Deficiency Syndrome

“…However, because the majority of DTDS patients have early onset in childhood, it is important to demonstrate the efficacy of our approach in neonate animals developing brain, as dopaminergic pathways development starts during early fetal stages41 and continues throughout peri- and post-natal phases4243. Nevertheless, some patients either display adult onset or reach the adult stage after childhood manifestation13, and therefore our approach already provide possibility for clinical development.…”

Expression of calbindin D28K in the dopaminergic mesotelencephalic system in embryonic and fetal human brain

“…We detected the first patches at 13 g.w. (Nobin and Björklund, 1973), the same stage as other patch‐matrix markers such as acetylcholinesterase, peptides, or D1‐D2 dopamine receptors were visualized (Brana et al, 1995, Brana et al, 1997; Aubert et al, 1997; Letinic and Kostovic, 1996). These different patch‐matrix markers were present before the appearance of the CaBP phenotype within the TH‐IR axons which occurred at midgestation, indicating that the TH axons of the patches could present functional properties before those of the matrix, as suggested in rodents (Gerfen et al, 1987).…”

Drugs, Biogenic Amine Targets and the Developing Brain

“…D 1 and D 2 receptors are measurable at these early prenatal time-points and increase in abundance throughout prenatal and early postnatal development to reach adult levels of expression between Postnatal day (P)14 and P21 in rodents (Sales et al 1989; Rao et al 1991; Schambra et al 1994; Caille et al 1995). In the monkey, DA receptors appear in target regions of DA input by the first quarter of gestation (Lidow et al 1991; Lidow 1995a) and in humans DA receptor binding sites have been detected by week twelve of gestation (Aubert et al 1997). Therefore, in all species examined, DA receptors are present very early in prenatal development, consistent with a role for DA in regulating neuronal differentiation and circuit formation.…”