The role of astrocytes in development and following injury in the CNS of transgenic mice

Astrocytes are one of the most versatile cell types in the CNS, exerting a spectrum of proposed functions from development through pathology. They guide cell migration and regulate growth and differentiation of neurons and oligodendrocytes in development. They are involved in forming and maintaining the blood brain barrier and buffering ions and neurotransmitter released during normal physiological processes. Astrocytes exhibit a remarkable response to injury that includes cell swelling, proliferating, hypertrophy, phagocytizing, glial scarring, and increasing production of glial fibrillary acidic protein (GFAP). To more fully understand the functions of astrocytes, we have utilized transgenic techniques to introduce novel genes and to "knock out" endogenous genes in astrocytes. We exploited several models that enabled us to label the nucleus of astrocytes with a lacZ reporter gene (Brenner et al., 1994), conditionally ablate astrocytes following treatment with a drug (Delaney et al., 1996), and eliminate the astrocyte specific cytoskeletal protein GFAP (McCall et al., 1996). Two major studies were undertaken to investigate the role of astrocytes in development of the cerebellum and the proliferative response of astrocytes following injury to the optic nerve.; Ablation of astrocytes during the first week postnatal, a critical period of cerebellar development, caused a number of abnormalities. The mice were ataxic, a phenotype associated with cerebellal defects. Histologic examination of their brains revealed cerebellar abnormalities consisting of reduced numbers of astrocytes, decreased granule cell neurons, and abnormal arborization of Purkinje cell dendritic trees. These effects were more severe following ablation at postnatal day 1 (P1) versus ablation at P5. These studies demonstrate that astrocytes have a critical role in development of cerebellar cytoarchitecture.; To examine the extent to which astrocyte proliferation contributes to the process of reactive astrocytosis, we injured the optic nerve of adult transgenic mice. LacZ labeled astrocytes were rigorously quantified with the optical disector, an unbiased stereologic technique. Astrocyte density did not increase following injury in normal and Gfap-null mice. The quantitation of astrocyte numbers demonstrates that they do not proliferate in response to injury of the optic nerve and that reactive astrocytosis in this structure depends on astrocytes hypertrophy more so than proliferation.