Spatial and temporal changes in natural and target deprivation-induced cell death in the mouse inferior olive

The survival of inferior olive neurons is dependent on contact with cerebel lar Purkinje cells. There is evidence that this dependence changes with tim e. Because inferior olivary axons, called climbing fibers, already show sig nificant topographical ordering in cerebellar target zones during late embr yogenesis in mice, the question arises as to whether olive neurons are depe ndent on target Purkinje cells for their survival at this early age. To bet ter characterize this issue, inferior olive development was studied in two transgenic mouse mutants, wnt-1 and L7ADT, with embryonic and early postnat al loss of cerebellar target cells, respectively, and compared to that in t he well-studied mutant, Lurcher. Morphological criteria as well as quantita tive measures of apoptosis were considered in this developmental analysis. Survival of inferior olive neurons is observed to be independent of Purkinj e cells throughout embryogenesis, but dependence begins immediately at birt h in both wild types and mutants. Thereafter, wild types and mutants show a rapid increase in olive cell apoptosis, with a peak at postnatal day 4, fo llowed by a period of low level, but significant, apoptosis that continues to at Least postnatal day 11; the main difference is that apoptosis is quan titatively enhanced in the mutants compared to wild types. The multiphasic course of these effects roughly parallels the known phases of climbing fibe r synaptogenesis. In addition, despite significant temporal differences amo ng: the mutants with respect to absolute numbers of dying cells, there are common spatial features suggestive of distinct intrinsic programs linking d ifferent olivary subnuclei to their targets. (C) 2000 John Wiley & Sons, In c. J Neurobiol 43: 18-30, 2000.