CONDITIONAL ABLATION OF CEREBELLAR ASTROCYTES IN POSTNATAL TRANSGENICMICE

Astrocytes have been proposed to have multiple roles in the developmen t and maintenance of the vertebrate CNS. To facilitate documentation o f these roles, we designed a transgene to enable their ablation at sel ectable times. The transgene consists of the coding region for the her pes simplex virus-thymidine kinase (HSV-TK) under the control of the h uman glial fibrillary acidic protein gene promoter. The HSV-TK is inno cuous but converts the antiherpetic agent ganciclovir (GCV) to a toxic product that interferes with DNA replication in proliferating cells. In a developmental study, transgenic mice were treated with GCV during the first postnatal week, with evaluation at P19. Treated mice displa yed severe ataxia. Histological examination revealed disrupted astrocy te development, particularly in the cerebellum with marked secondary e ffects on other cell types. cerebellar defects included a loss in the numbers of astrocytes and an overall reduction in cerebellar size and disruption of the normally well defined cellular layers. Radial glia w ere disordered, Purkinje cells were ectopically distributed and displa yed abnormal dendritic trees, and granule cells were markedly depleted . These effects were more severe in animals treated on postnatal day 1 versus treatment at day 5. A major factor causing granule cell death was excitotoxicity attributable to activation of NMDA receptors. These results suggest a critical role for astrocytes in cerebellar developm ent.