Anatomical, Physiological and biochemical studies of the cerebellum from reeler mutant mouse

Abstract 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.