Effects of the murine mutation 'nervous' on neurons in cerebellum and dorsal cochlear nucleus.

'Nervous' mutant mice are presently available on two different genetic background strains which are derived from out-breeding of the original BALB/cGr mutant stock. Light and electron microscopic studies of these mutants demonstrate that cerebellar Purkinje cells and cartwheel neurons of the dorsal cochlear nucleus (DCoN) show similar, albeit not identical, cytoplasmic and mitochondrial alterations in both background strains. In the cerebellar cortex, all Purkinje cell perikarya developed a varying number of enlarged and rounded mitochondria, as previously described. Extensive changes were observed in various components of the mitochondrial matrix. As cellular degeneration proceeded, reduction, fragmentation and dilation of cisterns of endoplasmic reticulum and the Golgi apparatus were evident. Some of the mitochondria underwent a peculiar type of degeneration, i.e. the outer membrane partially or completely dissolved, occasionally accompanied by focal interruptions of the inner membrane. In older adult mutants only 10% of cerebellar Purkinje cells rehained. The few surviving cells displayed varying states, ranging from essentially normal ultrastructure to electron-dense condensation. Many of these cells, in both strains, continued to display greatly enlarged, rounded mitochondrial profiles, indicating a change in the expression of the gene defect resulting from genetic contamination. Criteria for the identification of neuronal cell classes in layers 1 and 2 of murine DCoN were established. Cartwheel neurons in the mutant DCoN presented alterations similar to those observed in cerebellar Purkinje cells. The characteristic mitochondrial anomaly developed and proceeded in cartwheel neurons within a comparable time frame. The vast majority of affected cartwheel cells did not undergo degeneration, however, but continued to possess altered mitochondria into adulthood. The differences between normal and mutant mitochondria in Purkinje and cartwheel were quantified by morphometric analyses. Our findings lend support to the notion of a homology between cerebellar Purkinje cells and DCoN cartwheel cells. These cells represent major elements in two similar spatially related circuits, and share several genetic, structural and neurochemical properties. It is therefore proposed that these two cell populations are derived from closely related precursor cells.