NEURON DEATH IN THE SUBSTANTIA-NIGRA OF WEAVER MOUSE OCCURS LATE IN DEVELOPMENT AND IS NOT APOPTOTIC

Weaver is a spontaneous mutation in mice characterized by the postnata l loss of external granule cells in the cerebellum and dopaminergic ne urons of the midbrain, especially in the substantia nigra. We have sho wn previously that natural cell death with the morphology of apoptosis occurs in the substantia nigra of normal rodents during postnatal dev elopment. We therefore sought to determine whether the loss of dopamin ergic neurons in homozygous weaver mice occurs during the period of na tural cell death in the substantia nigra and whether it has the morpho logy of apoptosis. We have found, using a silver stain technique, that although apoptotic cell death does occur early postnatally in homozyg ous weaver substantia nigra, it also does so with equal magnitude in w ild-type and heterozygous weaver littermates. Unique to homozygous wea vers is the occurrence of degenerating neurons in the nigra that are n ot apoptotic. These degenerating neurons are observed at postnatal day 7, and they are most abundant on postnatal days 24-25. The nonapoptot ic nature of this cell death is confirmed by negative in situ end labe ling of nuclear DNA fragmentation and by ultrastructural analysis. Ult rastructural studies reveal irregular chromatin aggregates in the nucl eus, as well as marked cytoplasmic changes, including the formation of vacuoles and distinctive stacks of dilated cisternae of endoplasmic r eticulum. We interpret these changes as indicative of either a variant morphology of programmed cell death or a pathological degenerative pr ocess mediated by an as yet unknown mechanism related to the recently described mutation in the GIRK2 potassium channel.