Early development of the Lurcher cerebellum: Purkinje cell alterations and impairment of synaptogenesis

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Abstract
The postnatal development of the heterozygous Lurcher (Lc/+) mouse cerebellum is characterized by Purkinje cell death with a concomitant reduction in granule cell number. In order to evaluate possible relationships between these two events, this study investigates early morphological abnormalities of the Purkinje cells and possible defects in the formation of their synaptic investment. Cerebella of Lurcher and control age-matched (from P8 to P16) mice were analysed by calbindin immunostaining, silver impregnation and quantitative electron microscopy. Direct signs of Purkinje cell anomaly are obvious from P8, four days before the onset of the necrotic process. These signs include the presence of axonal swellings and perinuclear clumps of chromatin, and a general delayed process of maturation, evidenced in cell bodies (incomplete development of the basal polysomal mass) and in dendritic trees (hyperspinous dendrites, delayed formation of proximal and distal compartments). Also from P8, the external granular layer is reduced in thickness. Despite these abnormalities, the onset of the synaptogenesis between Purkinje cells and their specific inputs (parallel fibres, climbing fibres and basket cell axons) takes place on schedule and, at P8, no defect has been noticed. On and after P10, the rate of parallel fibre synaptogenesis is decreased. Very few climbing fibres translocate from their perisomatic to their peridendritic locations, and basket cell axons fail to develop ‘pinceau’ formations. All these results suggest that before the death of the Purkinje cell by P12, there is an impaired maturation of these neurons provoked by the Lurcher gene action. The hypoplasia of the external granular layer and the altered synaptic investment of the Purkinje cell after P10 are considered to be consequences of the early Purkinje cell defect.