Dopaminergic neurons in the mouse substantia nigra are replenished throughout the life of the animal, according to a report in the June 2 early online edition of PNAS. Moreover, the rate of neurogenesis can be experimentally stimulated, suggesting an attractive approach to replacing the nigral neurons lost in Parkinson's disease.
Other researchers have speculated that the stem cells lining the ventricles in the adult mammalian midbrain might give rise to new substantia nigra (SN) neurons, but an earlier study found evidence only for the birth of new glia in this area (Lie et al., 2002). In the current study, Ann Marie Janson, Jonas Frisen, and their colleagues at the Karolinska Institute in Stockholm, Sweden, present an impressive weight of evidence for adult SN neurogenesis, as well.
The researchers found signs of dying dopaminergic (DA) neurons in the SN throughout the adult lifetimes of the animals, without any change in the average number of DA neurons during adulthood. The most obvious solution to this conundrum-ongoing neurogenesis-was strongly supported by the finding of both immature and mature DA neurons in the SN that contained differentiation markers introduced by the researchers. Janson and her colleagues also used markers to show that these cells were derived from the ventricular area that contains stem cells.
"Although the number of neurons generated is orders of magnitude lower than in the hippocampus or the olfactory bulb, the estimated turnover rate implies, provided the rate is constant, that the entire population of dopaminergic substantia nigra neurons could be replaced within the life span of the mouse," write the authors.
But were these functional neurons? When the researchers injected tracers into the striatum-the area to which nigral DA neurons send projections-they found this tracer in the newly born neurons. Furthermore, when they injected cortical areas that are connected to the striatum, the tracers were relayed back to the newly born SN neurons, indicating that the cells had integrated themselves into the appropriate circuitry.
In a final experiment, which bodes well for the possibility of rescuing DA transmission in Parkinson's patients, the researchers killed about half the DA neurons with the toxin MPTP, and found that the rate of SN neurogenesis increased.
"The presence of a slow physiological turnover of neurons in the adult substantia nigra points to a functional role for neural stem cells in the midbrain. Moreover, the increased neuronal replacement observed after a partial nigral MPTP-induced lesion indicates that the rate of neurogenesis can be regulated," conclude the authors.
Beyond the therapeutic potential, the presence of the stem cells could offer a new spin on the pathogenesis of PD, write the authors. They suggest that the disorder could, in some cases, be caused by decreased neurogenesis, rather than increased neurodegeneration.—Hakon Heimer
- Lie DC, Dziewczapolski G, Willhoite AR, Kaspar BK, Shults CW, Gage FH. The adult substantia nigra contains progenitor cells with neurogenic potential. J Neurosci. 2002 Aug 1;22(15):6639-49. PubMed.
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- Zhao M, Momma S, Delfani K, Carlen M, Cassidy RM, Johansson CB, Brismar H, Shupliakov O, Frisen J, Janson AM. Evidence for neurogenesis in the adult mammalian substantia nigra. Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7925-30. PubMed.