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

Dopaminergic neurons in the substantia nigra pars compacta (SNpc) undergo n atural cell death during development in rats. Controversy exists as to the occurrence of this phenomenon in SNpe dopaminergic neurons in the developin g 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 SNpe vary in a time-dependent manner from postnat al day 2 to 32. These dying neurons also show evidence of DNA fragmentation , of activated caspase-3, and of cleavage of p-actin. Some, but not all of the SNpc apoptotic neurons still express their phenotypic marker tyrosine h ydroxylase, confirming their dopaminergic nature. Consistent with the impor tance of target-derived trophic support in modulating developmental cell de ath, we demonstrate that destruction of intrinsic striatal neurons by a loc al injection of quinolinic acid (QA) dramatically enhances the magnitude of SNpc apoptosis and results in a lower number of adult SNpe dopaminergic ne urons. Strengthening the apoptotic nature of the observed SNpc developmenta l cell death, we demonstrate that overexpression of the anti-apoptotic prot ein Bcl-2 attenuates both natural and QA-induced SNpc apoptosis. The presen t study provides compelling evidence that developmental neuronal death with a morphology of apoptosis does occur in the SNpc of mice and that this pro cess plays a critical role in regulating the adult number of dopaminergic n eurons in the SNpc. (C) 2000 Wiley-Liss, Inc.