“Stand by me”: astrocyte–microglia crosstalk in central nervous system development, homeostasis, injury, and disease

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, in the healthy adult CNS, astrocytes are known to play essential roles in maintaining homeostasis. Although the microglia primarily function as the resident immune cells of the CNS, it is now well established that these cells, together with the astrocytes, participate actively 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 neuroinflammatory responses and influences CNS damage progression. This review synthesizes current knowledge and provides updated insights into the mechanisms by which astrocytes and microglia communicate during embryonic development of the CNS, participate in network physiology in the adult CNS, and engage in cellular responses to disease, highlighting how their interactions contribute to pathology and enabling identification of potential avenues for therapeutic interventions. Specifically, we 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 to development and healthy adulthood. This observation reveals underexplored research avenues and emphasizes the need for studies addressing the roles of astrocyte-microglia interactions during physiological development and adult homeostasis. Finally, we briefly review novel approaches to overcome the difficulties of addressing astrocyte-microglia crosstalk.