Developmental cell death in dopaminergic neurons of the substantia nigra of mice

Vernice Jackson-Lewis, Miquel Vila, Ruth Djaldetti, Christelle Guegan, Gabriel Liberatore, Jian Liu, Karen L. O'Malley, Robert E. Burke, Serge Przedborski

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Abstract

Dopaminergic neurons in the substantia nigra pars compacta (SNpc) undergo natural cell death during development in rats. Controversy exists as to the occurrence of this phenomenon in SNpc dopaminergic neurons in the developing mouse. Herein, by using an array of morphologic techniques, we show that many SNpc neurons fulfill the criteria for apoptosis and that the number of apoptotic neurons in the SNpc vary in a time-dependent manner from postnatal day 2 to 32. These dying neurons also show evidence of DNA fragmentation, of activated caspase-3, and of cleavage of β-actin. Some, but not all of the SNpc apoptotic neurons still express their phenotypic marker tyrosine hydroxylase, confirming their dopaminergic nature. Consistent with the importance of target-derived trophic support in modulating developmental cell death, we demonstrate that destruction of intrinsic striatal neurons by a local injection of quinolinic acid (QA) dramatically enhances the magnitude of SNpc apoptosis and results in a lower number of adult SNpc dopaminergic neurons. Strengthening the apoptotic nature of the observed SNpc developmental cell death, we demonstrate that overexpression of the anti-apoptotic protein Bcl-2 attenuates both natural and QA-induced SNpc apoptosis. The present study provides compelling evidence that developmental neuronal death with a morphology of apoptosis does occur in the SNpc of mice and that this process plays a critical role in regulating the adult number of dopaminergic neurons in the SNpc. 2000 Wiley-Liss, Inc.

Original languageEnglish
Pages (from-to)476-488
Number of pages13
JournalJournal of Comparative Neurology
Volume424
Issue number3
DOIs
StatePublished - Aug 28 2000

Keywords

  • Apoptosis
  • Bcl-2
  • Dopamine
  • Excitotoxicity
  • GABA
  • Postnatal development
  • Target derived support
  • Trophic factors

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    Jackson-Lewis, V., Vila, M., Djaldetti, R., Guegan, C., Liberatore, G., Liu, J., O'Malley, K. L., Burke, R. E., & Przedborski, S. (2000). Developmental cell death in dopaminergic neurons of the substantia nigra of mice. Journal of Comparative Neurology, 424(3), 476-488. https://doi.org/10.1002/1096-9861(20000828)424:3<476::AID-CNE6>3.0.CO;2-0