CELL-DEATH IN THE MIDBRAIN OF THE MURINE MUTATION WEAVER

The midbrain of the adult homozygous weaver (wv/wv) mouse is notable f or a reduction in the numbers of dopamine-containing cells in the subs tantia nigra (A9) and the retrorubral nucleus (A8). We have determined that the reduction in tyrosine hydroxylase (TH)-positive neurons in t he ventral midbrain of the weaver is attributable to the loss of neuro ns after postnatal day 7 (P7). Because the number and spatial distribu tion of TH-positive mesencephalic neurons in wv/wv, heterozygous weave rs (+/wv), and wild-type mice are not significantly different on P7, w e conclude that the early developmental steps of proliferation and mig ration have taken place normally in the mutant. Although numbers and d istribution of cells are normal in the wv/wv on P7, the appearance of the TH-stained ventral midbrain is abnormal because of the paucity of TH-stained dendritic processes. The ventrally extending TH-positive de ndrites are largely absent in the young wv/wv. The wv/wv also can be d istinguished from both homozygous normal (+/+) and wv/wv littermates o n P7 based on the appearance of dendrites that are more numerous than in the wv/wv but thin, disorganized, and sparse compared with +/+. Mos t cell death seems to lake place in wv/wv before P21. However, at leas t one subset of dopamine-containing neurons disappears later. The zone of densely packed TH-positive neurons in the substantia nigra that is likely to be the origin of innervation to striosomes in the caudoputa men disappears between P21 and adulthood. Despite the early pathology evident in the mesencephalic dopamine-producing neurons of the +/wv, n o evidence for cell death was observed there even in the oldest +/wv w eavers studied.