Brainstem motor nuclei respond differentially to degenerative disease in the mutant mouse wobbler.

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Degenerative motoneurone diseases, whether in humans, animals, or transgenic mouse models, do not affect all types of motoneurone to the same degree. Understanding the relative differences in vulnerability of certain motor pools may be the key to developing therapies. Expression of calbindin (CB) and parvalbumin (PV) immunoreactivity, which are potentially neuroprotective calcium-binding proteins, and NADPH-diaphorase (NADPH-d) histochemical reactivity, a marker for neurodegeneration, was studied in brainstem sections from mutant wobbler mice and their normal littermates during the motoneurone degeneration phase (3-8 weeks of age). The motor trigeminal and facial nuclei reacted in a manner previously observed in spinal somatic motoneurones in the wobbler. Many motoneurones expressed moderate NADPH-d reactivity, correlated with the appearance of vacuolated motoneurones in Nissl-stained sections. This was not observed in littermate controls. Motoneurone counts from Nissl-stained sections from 14-month-old wobblers and littermates revealed significantly fewer (approximately 27%) motoneurones in the trigeminal nucleus of wobblers. In contrast, the wobbler hypoglossal nucleus contained neither vacuolated nor NADPH-d reactive motoneurones. However, expression of CB immunoreactivity by the majority of wobbler hypoglossal motoneurones was observed but not in littermate controls or in any other motor nucleus. Counts in older animals showed a smaller but still significant difference in motoneurone number between wobblers and controls (approximately 9% reduction). Finally, the wobbler abducens nucleus displayed neither vacuolated neurones, nor NADPH-d reactivity nor CB immunoreactivity. Motor nuclei innervating extraocular muscles appear to be protected in many forms of motoneurone disease in man and other species. However, there were still markedly fewer abducens motoneurones in the old wobblers compared to controls (approximately 29% reduction). Sparing of oculomotor neurones in other diseases has been attributed to their relatively high PV expression, which we also observed in the abducens nucleus of both wobblers and littermates, and to a lesser extent in the other motor nuclei too. In conclusion, our results suggest that, in the wobbler mouse, motoneurone degeneration may occur without overt signs such as cell body vacuolation and NADPH-d expression. Induced CB expression may be neuroprotective but that constitutive expression of PV may not.