Progressive atrophy of cerebellar Purkinje cell dendrites during aging of the heterozygous staggerer mouse ( Rora+/sg)

Abstract

Staggerer ( Rora sg/sg) is an autosomal mutation in an orphan nuclear hormone receptor gene, RORalpha, that acts intrinsically within the Purkinje cells and causes dysgenesis of the cerebellar cortex. Purkinje cell number is severely reduced, and the surviving cells are small with poorly developed dendrites. In contrast, the cytoarchitecture of the cerebellar cortex of the heterozygous staggerer ( Rora +/sg) appears to be normal. However, quantitative studies have revealed a premature loss of Purkinje cells with advancing age. Most of the loss (25–30%) is complete by 13 months with little change thereafter. To address the question of whether all Purkinje cells, even the surviving ones, are affected by aging even though their cell bodies remain intact, we studied the evolution with age of the dendritic arbor through a semi-quantitative analysis of Golgi-impregnated Purkinje cells. A total of ten different morphological parameters were measured in 4-, 12- and 22-month-old wild type and heterozygous Rora +/sg mice. While the effects of the aging process are apparent in the wild type cerebellum, they are considerably accelerated in the Rora +/sg mouse. By 12 months the Rora +/sg Purkinje cell dendrite is as atrophic as a wild type dendrite from a 22-month-old and the dendritic regression continues well beyond the period of cell death in the heterozygous Rora +/sg mouse.