Astrocytes conspire with neurons during progression of neurological disease

Abstract

As astrocytes are becoming recognized as important mediators of normal brain function, studies into their roles in neurological disease have gained significance. Across mouse models for neurodevelopmental and neurodegenerative diseases, astrocytes are considered key regulators of disease progression. In Rett syndrome and Parkinson's disease, astrocytes can even initiate certain disease phenotypes. Numerous potential mechanisms have been offered to explain these results, but research into the functions of astrocytes in disease is just beginning. Crucially, in vivo verification of in vitro data is still necessary, as well as a deeper understanding of the complex and relatively unexplored interactions between astrocytes, oligodendrocytes, microglia, and neurons.

Figure 1. Genetic Strategies for Recessive Diseases

When trying to determine the role of astrocytes in Rett syndrome, our lab used the genetic strategies outlined here. These strategies are designed to cause knockouts after the shared neural progenitor stage (Nestin+, GFAP+) by inducing excision in differentiated neurons (Synapsin::Cre is merely one example) or differentiated astrocytes (hGFAP::CreER^T2 + tamoxifen). In this figure, Your Favorite Gene (YFG) takes the place of MeCP2 from Rett. Blue indicates normal expression levels and black indicates low or no expression. While useful, no Cre line is expressed in 100% of the cell type indicated, and the extent of mosaic expression will influence the interpretation of results.

Figure 2. Genetic Strategies for Dominant Diseases

Similar to Figure 1, these genetic strategies are designed to express the dominant gene of interest (Dom) only after the shared neural progenitor stage. Blue indicates wild type gene expression and red indicates expression or overexpression of the dominant gene. Again, mosaic expression of Cre recombinase will influence result interpretation.