Nerve cell atrophy and loss in the inferior olivary complex of “Purkinje cell degeneration” mutant mice

Abstract

The genetically determined loss of cerebellar Purkinje cells (PCs) in "Purkinje cell degeneration" (pcd) mutant mice deprives inferior olivary (IO) neurons of their major postsynaptic target. The degeneration of PCs starts on postnatal day (P) 17 and loss of these neurons is virtually complete by P45. We examined the inferior olivary complex (IOC) of normal and pcd mutant mice by quantitative light microscopy to determine whether the degeneration of PCs is associated with atrophy and loss of their presynaptic neurons in the IOC. The number of IO neurons in 17-day-old mutants did not differ significantly from controls (P greater than .1). IO neurons in 23-day-old mutants were 23% (95% confidence limits: 12-34%) fewer than in age-matched controls, and in 300-day-old mutants they were 48% (95% confidence limits: 37-58%) fewer than in their controls (P less than .001 in both cases). The decline of the number of IO neurons in pcd mice between days 17 and 300 was 49% (P less than .0001; 95% confidence limits: 38-57%). The medial accessory olive (MAO) appeared less affected than the principal (PO) and the dorsal accessory olive (DAO). The mean neuronal diameter in control mice was 11.6 micron at 23 days and 10.8 micron at 300 days of age. The respective values in pcd mutants were 11.5 micron and 8.7 micron. Diameters in old mutants were significantly smaller than those in both age-matched controls and young mutants (P less than .001). These findings suggest that in the mature olivocerebellar system the stability of IO neurons depends on the state of their postsynaptic PCs.

SUPPRESSEDNNA1GENE EXPRESSION IN THE BRAIN OF ATAXIC SYRIAN HAMSTERS

“…With regard to the latter, and as in the case of our ataxic hamsters, pcd-mutant mice show adultonset degeneration of cerebellar Purkinje neurons (Mullen et al, 1976) and a slow, progressive degeneration of granule cells, probably due to the primary degeneration of Purkinje cells (Triarhou et al, 1985). These mutant mice also display progressive partial degeneration of retinal photoreceptor cells (La Vail et al, 1982), mistal neurons in olfactory bulbs (Greer et al, 1982), inferior olivary neurons (Ghetti et al, 1987), and selected thalamic neurons (O'Goman and Sidman, 1985), and exhibit defective spermatogenesis (Mullen et al, 1976). Such histological abnormalities in pcd mutant mice become obvious at more than one year of age.…”

The Ataxic Syrian Hamster: An Animal Model Homologous to the pcd Mutant Mouse?

“…In the thalamus, for example, selected populations of thalamic neurons begin to degenerate at 7 to 9 weeks of age [34,35]. Neurons in both the inferior olivary complex and the deep cerebellar nuclei of the pcd 1J mice appear to be affected by the Purkinje cell loss, since these neurons normally establish synaptic contacts with the Purkinje cells [36]. Indeed, secondary, trans-neuronal degeneration profiles, i.e., a reduction in cell number and substantial cell atrophy, are observed in these regions of the old mutants [36,37].…”

“…Neurons in both the inferior olivary complex and the deep cerebellar nuclei of the pcd 1J mice appear to be affected by the Purkinje cell loss, since these neurons normally establish synaptic contacts with the Purkinje cells [36]. Indeed, secondary, trans-neuronal degeneration profiles, i.e., a reduction in cell number and substantial cell atrophy, are observed in these regions of the old mutants [36,37]. Of the sensory organs, retinal photoreceptor cells [13,38] and mitral neurons in olfactory bulbs [13,39] are affected in the pcd 1J mice.…”

Cell Interactions Underlying Purkinje Cell Replacement by Neural Grafting in the pcd Mutant Cerebellum

“…In order to determine whether or not grafted PCs are able to recapitulate their developmental history within the adult host cerebellum, short-term survivals have been analyzed in a timed sequence from 3 up to 21 days after grafting (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21), to compare at a given age the stage of maturation of the grafted PCs with that normally occurring in cerebellar ontogenesis.…”