Molecular mechanisms regulating glia homeostasis

Abstract

Microglia are resident myeloid cells of the central nervous system that are critical for brain functioning in health and disease. Using tissue-specific conditional gene targeting in mice, together with other methodologies, we have revealed essential functions for the of the Rho family of GTPases in regulating microglia homeostasis and brain physiology. In particular, we showed that microglia-specific ablation of RhoA in adult mice profoundly disrupted the homeostasis of brain microglia, resulting in the production of several mediators of inflammation, including reactive oxygen species, which impaired long-term synaptic plasticity and led to cognitive deficits. We found that RhoA exerted its microglial homeostatic functions by sustaining C-terminal Src kinase (Csk) negative regulation of c-Src tyrosine kinase activity. Accordingly, inhibition of Src with a clinically-relevant inhibitor almost completely restored microglia homeostasis and normal cognitive performance. Overall, our work demonstrates that the RhoA/Csk/Src pathway regulates microglia function, and further highlights the essential and primary role of microglia as gatekeepers of adult brain physiology.