Evidence that nigral dopaminergic neurogenesis does not occur in the adult

Several independent groups have tried unsuccessfully to obtain evidence of spontaneous generation of BrdU+ TH+ neurones in the substantia nigra of normal unlesioned adult rats (Lie et al. 2002; Frielingsdorf et al. 2004; Chen et al. 2005; Mohapel et al. 2005; Reimers et al. 2006) and mice (Kay and Blum 2000; Mao et al. 2001; Frielingsdorf et al. 2004). Some groups found BrdU+ nuclei located immediately adjacent to the TH+ neurones that seemed to be associated with TH+ cell bodies (16–20 nuclei per substantia nigra), but careful analysis by confocal z-series of each of these cells revealed that the BrdU+ nuclei were in cells that were in close proximity to TH+ neurones (Lie et al. 2002; Frielingsdorf et al. 2004; Mohapel et al. 2005). Moreover, Frielingsdorf et al. (2004) convincingly showed that the BrdU+ nuclei were not in the TH+ neurones with NeuN+ nuclei.

Five different groups also tried unsuccessfully to provide evidence that the loss of dopaminergic cells induced in rats by the injection of 6-OHDA into either the medial forebrain bundle (Lie et al. 2002; Cooper and Isacson 2004; Frielingsdorf et al. 2004; Mohapel et al. 2005; Reimers et al. 2006) or the striatum (Steiner et al. 2006) induces neurogenesis in the substantia nigra. Negative results were also obtained following acute (Kay and Blum 2000; Höglinger et al. submitted) and subacute (Mao et al. 2001; Höglinger et al. submitted) intoxication with MPTP. Profuse gliogenesis, however, has been reported in the substantia nigra and in the striatum after 6-OHDA-lesions in rats (Chen et al. 2002; Steiner et al. 2006) and MPTP-lesions in mice (Mao et al. 2001; Chen et al. 2004).

The effect of growth factors on dopaminergic neurogenesis in the adult substantia nigra has also been investigated. No evidence for the generation of BrdU+ TH+ neurones was found after chronic infusion of glia-derived neurotrophic factor (GDNF) into the striatum of adult rats, although the number of nigral TH+ neurones increased by 32%, which was most likely the result of the induction of a dopaminergic phenotype in pre-existing neurones (Chen et al. 2005). Similarly, no TH+ BrdU+ double-labelled neurones were observed in either the lesioned or the unleasioned substantia nigra of 6-OHDA-treated rats after 4 weeks of the intrastriatal infusion of transforming-growth factor α (TGFα) (Cooper and Isacson 2004). Intraventricular infusion of either brain-derived neurotrophic factor (BDNF) or platelet-derived neurotrophic factor (PDGF) for 10 days was also ineffective in generating BrdU+ TH+ neurones in the substantia nigra of adult rats either with or without 6-OHDA lesions (Frielingsdorf et al. 2004; Mohapel et al. 2005), as was the intrastriatal infusion of liver growth factor (LGF) (Reimers et al. 2006).

Conclusion and perspectives


In the last two years a large body of converging data have consistently shown that the neurotransmitter dopamine stimulates endogenous adult neurogenesis in the SVZ by activating D2-like receptors on transit-amplifying progenitor cells. It remains to be studied in detail, however, whether the decreased neurogenesis in diseases such as PD, which are characterized by dopamine depletion, has clinically relevant functional consequences. Nevertheless, as precursor cells in the adult mammalian brain are pharmacologically accessible to the systemic administration of dopamimetic drugs, the stimulation of endogenous neurogenesis appears to be a potential strategy for a cell replacement therapy of the brain in diseases in which SVZ-derived cells appear to contribute to repair processes (Arvidsson et al. 2002; Picard-Riera et al. 2002; Curtis et al. 2003; Jin et al. 2004).

In contrast, the existence of neurogenesis in vivo in the adult mammalian substantia nigra remains controversial, although progenitor cells that can differentiate into neurones are present (Lie et al. 2002). The species of rodent studied, the manner in which BrdU was administered, or the delay between mitotic labelling and analysis might explain some discrepancies. Other confounding factors are summarized in Table 1. Because of the chronic progression of neuronal cell loss in PD, the therapeutic interest of stimulating adult neurogenesis in the substantia nigra is great, but the genesis in vivo of dopaminergic neurones in the substantia nigra from precursor cells in the adult mammalian brain has yet to be unequivocally demonstrated, dampening for the present our enthusiasm for this therapeutic approach.