Cerebellar Purkinje Cell Loss During Life Span of the Heterozygous Staggerer Mouse ( Rora  /Rora sg ) is Gender-Related MOHAMED DOULAZMI, * FLORENCE FRE ´ DE ´ RIC, YOLANDE LEMAIGRE-DUBREUIL, NADIA HADJ-SAHRAOUI, NICOLE DELHAYE-BOUCHAUD, AND JEAN MARIANI Laboratoire de Neurobiologie du De ´ veloppement, Institut des Neurosciences (UMR 7624 CNRS), Universite ´ P. & M. Curie, 75005 Paris, France. ABSTRACT The staggerer mutation causes dysgenesis of the cerebellar cortex in the homozygous mutant (Rora sg /Rora sg ). The mutation acts intrinsically within the Purkinje cells (PCs), leading to cytological abnormalities and a severe deficit in the number of these cells. In contrast, in the heterozygous staggerer (Rora + /Rora sg ), the cytoarchitecture of the cerebellar cortex appears to be normal, but quantitative studies have revealed a significant loss of cerebellar neurons with advancing age. In the heterozygous reeler (+/rl), another mutant presenting a PC loss with age, we have found that only males were affected (Hadj-Sahraoui et al., 1996). In the present study, we have investigated whether a similar gender effect exists in the heterozygous staggerer during life span. PCs were counted on cerebellar sagittal sections in male and female Rora + /Rora sg and in their Rora + /Rora + littermates at 1, 3, 9, 13, 18, and 24 months of age. In the Rora + /Rora + , the number of PCs remained stable until 18 months, but there was a 25% significant loss in 24- month-old mice of both genders. During life span, Rora + /Rora + males had slightly more PC than females. In the Rora + /Rora sg of both genders, the deficit in PC number was similar at 13 months but it appeared earlier in males, beginning between 1 and 3 months, and was aggravated regularly up to 13 months. By contrast, the decline was delayed and more abrupt in Rora + /Rora sg females, from a value still normal at 9 months to its maximal extent at 13 months. In view of these results, the heterozygous (Rora + /Rora sg ) mouse offers an interesting model to test the interaction between sex, age, and genetic background on the development and maintenance of cerebellar neuronal populations. J. Comp. Neurol. 411:267–273, 1999.  1999 Wiley-Liss, Inc. Indexing terms: aging; neuronal death; mutant mice; cerebellum Several mutations have been described in mice, which lead to neuronal degeneration in the cerebellum. The staggerer mutation, located on chromosome 9, affects the ROR gene, a nuclear receptor gene which, in the cerebel- lum, is expressed only in Purkinje cells (PC) (Becker- Andre et al., 1993; Giguere et al., 1994; Hamilton et al., 1996; Steinmayr et al., 1998). The homozygous staggerer mouse has a severe ataxia and its cerebellum is markedly atrophied, with poorly developed folia (Sidman et al., 1962). The mutation causes a severe deficit in the number of PCs (Herrup and Mullen, 1979) with cytological abnor- malities in the remaining ones. In addition, all of the granular cells and 60% of the inferior olivary neurons die during the first postnatal month, presumably because of the loss of their common target, the PCs (see review of literature in Zanjani et al., 1990, 1994; Herrup et al., 1996). In contrast, the heterozygous staggerer (Rora + / Rora sg ) shows no apparent ataxia, and the cytoarchitec- ture of its cerebellar cortex appears to be normal. However, previous quantitative studies showed that the Rora + / Rora sg mouse undergoes a significant loss of cerebellar neurons with advancing age. The cell loss affects the same neuronal populations in Rora + /Rora sg as in the homozy- gous mutant, but the deficit has a late onset and is progressive from a normal cell number at 3 months of age to a deficit of about 25–30% of the PCs and granule cells and 40% of the olivary neurons at 12 months (Shojaeian et Grant sponsor: FMR: Grant ‘‘vieillissement’’; Grant sponsor: Biomed 2 European program; Grant number: ‘‘cybrainet’’ BMH-C97–2492. *Correspondence to: Mohamed Doulazmi, Laboratoire de Neurobiologie du De ´veloppement, Institut des Neurosciences (UMR 7624 CNRS), Universite ´ P. & M. Curie, 75005 Paris, France. E-mail: mohamed.doulazmi@snv.jussieu.fr Received 23 December 1998; Revised 15 March 1999; Accepted 22 March 1999 THE JOURNAL OF COMPARATIVE NEUROLOGY 411:267–273 (1999)  1999 WILEY-LISS, INC.