- Awarded: 2015
- Award Type: Pilot
- Award #: 346154
Dysregulation of the normal immune response appears to underlie the development of a wide variety of neurodegenerative diseases, including autism spectrum disorders (ASDs). Animal models of ASD have demonstrated that maternal infection or abnormal immune signaling contribute to the development of autism-like disorders. Together, these findings suggest that immune response genes play an important role in the generation of ASDs.
Rett syndrome is a devastating neurodevelopmental disorder that almost exclusively affects girls. In many cases, Rett syndrome is caused by mutations in the methyl-CpG-binding protein 2 (MeCP2) gene, which encodes a protein that regulates the expression of many other genes. Without MeCP2, the expression of genes under its control is drastically altered, which disrupts normal brain development and function. A common feature in ASD, including Rett syndrome, is an unusually high production level of cytokines1,2. As important regulators of the inflammatory response of the body, cytokines are generally produced upon infection or wounding, as their prolonged production can cause damage to the body.
Microglia and astrocytes are the two cell types that are responsible for regulating inflammatory responses in the brain. Alysson Muotri and his colleagues — collaborators on the current study — have generated astrocytes lacking a functional MeCP2 gene by culturing cells isolated from individuals with Rett syndrome. These Rett syndrome astrocytes produced an abnormally large amount of cytokines in culture. An outstanding question is how the lack of MeCP2 affects the functioning of microglia, astrocytes and neurons in the complex environment of a living brain.
The zebrafish model system allows live-imaging of the behavior of these cells inside the brain, by visualizing directly each cell type labeled with different fluorescent proteins. David Traver and his team at the University of California, San Diego plan to use zebrafish with a mutation in their MeCP2 gene to investigate how cellular behavior and gene expression levels are altered in this model of Rett syndrome3. The overall goal of these studies is to help identify new drugs that may ultimately treat individuals with Rett syndrome and other ASDs.