The cerebellum of the homozygous reeler mouse shows a marked reduction in size and in the number of fissures, its dry mass and DNA content are respectively and j—J of those of normal animals. Its high content in the P400 protein, which is abundant in the Purkinje cell, indicates that the decrease in cell number associated with the fall in DNA affects primarily the granular cells. The anatomy of the reeler cerebellum is rather unique: a thin cortex with almost normal molecular, granular and Purkinje cell layers embracing a central mass of closely packed large neurons, mostly Purkinje cells. Purkinje cells may therefore be found in four different cellular environments: (1) at their normal position in the superficial cortical structure; (2) within the granular layer; (3) intermingled with white matter in the central mass; (4) overlapping with neurons of the deep cerebellar nuclei. The reeler cerebellum therefore offers a model to study to what extent local cellular interactions are required to achieve the planar organization of the Purkinje cell dendrites and the normal synaptic investment of these cells. Concerning the three-dimensional shape of Purkinje cells, only the rare ones located at their normal position and receiving a normal ratio of all their synaptic afferences succeed to develop a characteristic dendritic pattern. Purkinje cells within the granular layer show three distinct patterns of dendritic arrangements. The variation in shape of the Purkinje cell dendrites located in the central agranular mass mimics that described in other agranular cerebella: in particular they show randomly oriented dendrites devoid of spiny branchlets. Concerning the cerebellar circuitry, the specificity of most of the synaptic connections is preserved, despite important disorders in Purkinje cell distribution.Several important differences with the normal cerebellum have, however, been observed at the level of the Purkinje cell: (i) The density of climbing fibre varicosities increases in the central cerebellar mass, where Purkinje cells are deprived of parallel fibre afferences. In addition, electrophysiological studies reveal that, at this position, the response of the Purkinje cells to climbing fibre stimulation is graded by steps as a function of stimulus intensity instead of being all-or-none as found in the superficial cortex or in normal cerebellum. These deep Purkinje cells receive therefore several climbing fibres instead of only one as in normal adult cerebellum, (ii) Ectopic synapses (somato-dendritic and dendro-dendritic) between the soma and/or the dendrite of the granule cell as presynaptic element and mainly the Purkinje cell dendrites as postsynaptic element may form, (iii) Heterologous synapses between mossy fibres and Purkinje cell spines are found in the granular layer and within the central mass. The electrophysiological studies show that these synapses are functional.

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Retinoid-related orphan receptor α (RORα) is a member of the nuclear receptor superfamily. To study its physiological role we generated null-mutant mice by targeted insertion of a lacZ reporter gene encoding the enzyme β-galactosidase. In heterozygous RORα ^+/− mice we found β-galactosidase activity, indicative of RORα protein expression, confined to the central nervous system, skin and testis. In the central nervous system, the RORα gene is expressed in cerebellar Purkinje cells, the thalamus, the suprachiasmatic nuclei, and retinal ganglion cells. In skin, RORα is strongly expressed in the hair follicle, the epidermis, and the sebaceous gland. Finally, the peritubular cells of the testis and the epithelial cells of the epididymis also strongly express RORα. Recently, it was reported that the ataxic mouse mutant staggerer ( sg / sg ) is caused by a deletion in the RORα gene. The analysis of the cerebellar and the behavioral phenotype of homozygous RORα ^−/− mice proves identity to sg / sg mice. Although the absence of RORα causes dramatic developmental effects in the cerebellum, it has no apparent morphological effect on thalamus, hypothalamus, and retina. Similarly, testis and skin of RORα ^−/− mice display a normal phenotype. However, the pelage hair of both sg/sg and RORα ^−/− is significantly less dense and when shaved shows reluctance to regrow.

We previously generated a mouse model with a mutation in the murine Atm gene that recapitulates many aspects of the childhood neurodegenerative disease ataxia-telangiectasia. Atm -deficient ( Atm −/−) mice show neurological defects detected by motor function tests including the rota-rod, open-field tests and hind-paw footprint analysis. However, no gross histological abnormalities have been observed consistently in the cerebellum of any line of Atm −/− mice analyzed in most laboratories. Therefore, it may be that the neurologic dysfunction found in these animals is associated with predegenerative lesions. We performed a detailed analysis of the cerebellar morphology in two independently generated lines of Atm −/− mice to determine whether there was evidence of neuronal abnormality. We found a significant increase in the number of lysosomes in Atm −/− mice in the absence of any detectable signs of neuronal degeneration or other ultrastructural anomalies. In addition, we found that the ATM protein is predominantly cytoplasmic in Purkinje cells and other neurons, in contrast to the nuclear localization of ATM protein observed in cultured cells. The cytoplasmic localization of ATM in Purkinje cells is similar to that found in human cerebellum. These findings suggest that ATM may be important as a cytoplasmic protein in neurons and that its absence leads to abnormalities of cytoplasmic organelles reflected as an increase in lysosomal numbers.

In Alzheimer disease, a combination of genetic predisposition and environmental factors may contribute to changes in beta-amyloid precursor protein (APP) expression, beta-amyloid peptide deposition, and neuronal loss. Factors such as head injury or acute infection that trigger inflammatory processes may play a crucial role in development of the disease. In the present in vivo study, we showed that, in mouse brain, peripheral stimulation with lipopolysaccharide (LPS) induced a transient increase in the inflammatory cytokine mRNAs (interleukin 1 beta and interleukin 6), followed by changes in expression of APP isoforms in the cerebellum but not in the cerebral cortex. These changes consisted of a decrease in the APP-695 and an increase in the Kunitz protease inhibitor-bearing isoforms (KPI-APP). In the cerebellum of the staggerer mouse mutant, where a severe loss of Purkinje and granule cells occurs, basal mRNA levels of these interleukins were elevated and an increase in the KPI-APP/APP-695 ratio compared to wild-type mice was observed. These abnormalities were further accentuated by LPS stimulation. This study shows that acute and chronic inflammatory processes play an important role in changes in APP expression possibly associated with neurodegeneration.