Axonal abnormalities in cerebellar Purkinje cells of the 'hyperspiny Purkinje cell' mutant mouse.

The hyperspiny Purkinje cell (hpc) is a murine, autosomal recessive mutation affecting cerebellar Purkinje cells. Axonal abnormalities in these neurons have been revealed by selective silver impregnation, specific immunohistochemical staining and electron microscopy. The main pathological feature consists of a massive axonal degeneration in the terminal domains of the Purkinje cell projection. This process starts approximately ten days postnatally, simultaneously with the onset of cerebellar symptoms, and evolves very rapidly. By 21 days, the vast majority of the terminal arbors have degenerated, resulting in an almost complete disruption of the corticonuclear projection. Axonal degeneration, although proceeding in a dying-back fashion, only provokes retrograde death in a small percentage of Purkinje cells (less than 15%). Purkinje cells exhibit other signs of axonal damage and axonal reaction: (a) Almost all of them bear gigantic varicosities (spheroids or torpedoes) along their transit through the granular layer. (b) In a small percentage of cases, a dendritic segment is inserted between the axon hillock and the initial segment (meganeurite). These ectopic dendrites receive a normal contingent of synaptic inputs, and are transient structures observed in four- to six-week-old mice. (c) The infra- and supraganglionic plexuses, formed by recurrent collaterals of Purkinje cell axons, have increased density and terminal domains. (d) In mice aged over 50 days, many Purkinje cells have developed 'arciform' axons, which is evidence of a compensatory reaction. The definite axonal pathology of hpc Purkinje cells confers to this mutation its own specificity, which differs from all other known mutations primarily affecting this neuronal population. Therefore, the hpc mutation offers a valuable tool to analyse some of the genetic factors involved in the differentiation and maintenance of cerebellar Purkinje cells.