"Stand by Me": Astrocyte–Microglia Crosstalk in CNS development, homeostasis, Injury and Disease

Abstract

During central nervous system (CNS) development, astrocytes and microglia arise from distinct embryonic origins; however, during early development, both cell types coordinately participate in brain circuit formation and neuronal network establishment. Later on, in the adult healthy CNS, astrocytes are known to play essential roles in maintaining homeostasis. While microglia primarily function as the resident immune cells of the CNS, it is now well established that these cells, together with astrocytes, actively participate in synaptic regulation, neuronal circuitry functioning, and cognition. In response to acute injury or chronic disease, both cell types undergo profound phenotypic changes and engage in a dynamic, bidirectional crosstalk that critically shapes the neuroinflammatory response and influences CNS damage progression. This review synthesizes current knowledge and provides updated insights into the mechanisms by which astrocytes and microglia communicate during CNS embryonic development, participate in network physiology in the adult CNS, and engage in cellular response to disease, highlighting how their interactions contribute to pathology and identifying potential avenues for therapeutic intervention. We specifically have focused on reviewing articles that directly address astrocyte-microglia communication. As an interesting outcome of our literature survey, we identified a significant bias toward studies investigating astrocyte–microglia crosstalk in pathological contexts compared with development and healthy adulthood. This observation reveals underexplored research avenues and emphasizes the need for studies addressing the role of astrocyte–microglia interactions during physiological development and adult homeostasis. Finally, this article will briefly review novel approaches to overcome the difficulties of addressing astrocyte-microglial crosstalk.