ABNORMAL ASTROCYTE DIFFERENTIATION AND DEFECTIVE CELLULAR INTERACTIONS IN WOBBLER MOUSE SPINAL-CORD

The wobbler mutation is inherited as an autosomal recessive trait and displays a muscular atrophy associated with motoneuron degeneration in early postnatal development. It has been shown that the level of glia l fibrillary acidic protein (GFAP) is greatly increased in the spinal cord of wobbler mice. We performed immunocytochemical analyses combine d with confocal microscopy to study the developmental distribution of GFAP-positive astrocytes in the spinal cord of wobbler mice during the course of the disease, and in primary cultures of adult wobbler spina l cord astrocytes. Many changes in the number and distribution of astr ocytes were observed in the wobbler mice from 1-10 months post-partum Strongly GFAP-positive astrocytes are present in small number in the a nterior horn by 1 month. They increase in number and are observed in t he entire spinal cord grey and white matters by 2-10 months. These rea ctive astrocytes have thick, short, extensively branched processes whi ch contrast with the long, unbranched processes observed in control mi ce. The wobbler astrocyte processes are oriented perpendicular to the surface of the spinal cord, which contrasts with the normal parallel, concentric orientation. No expansion of astrocyte processes exit from the white matter towards the grey matter. Moreover, the surface of the wobbler spinal cord beneath the meninges displays a dramatic decrease of interdigitating processes, end feet and flattened cell bodies of a strocytes that form a disorganized layer. In vitro, mutant astrocytes have morphological characteristics similar to those in vivo and, in pa rticular, develop short, thick, branched processes. These mutant astro cytes in cultures do not contact one another, whereas normal mature cu ltures show an increased incidence of cell-cell contacts between long processes. The increase of astrocyte reactivity associated with these modifications in astrocytic process arrangement may reflect an importa nt primary event in the course of the wobbler disease rather than a no n-specific response to motoneuronal death.