Astroglial cells are key to maintain nervous system homeostasis. Neurotrophins are known for their pleiotropic effects on neuronal physiology but also exert complex functions to glial cells. Here, we investigated (i) the signaling competence of mouse embryonic and postnatal primary cortical astrocytes exposed to brain-derived neurotrophic factor (BDNF) and, (ii) the role of kinase D-interacting substrate of 220 kDa (Kidins220), a transmembrane scaffold protein that mediates neurotrophin signaling in neurons. We found a shift from a kinase-based response in embryonic cells to a response predominantly relying on intracellular Ca2+ transients [Ca2+]i within postnatal cultures, associated with a decrease in the synthesis of full-length BDNF receptor TrkB, with Kidins220 contributing to the BDNF-activated kinase and [Ca2+]i pathways. Finally, Kidins220 participates in the homeostatic function of astrocytes by controlling the expression of the ATP-sensitive inward rectifier potassium channel 10 (Kir4.1) and the metabolic balance of embryonic astrocytes. Overall, our data contribute to the understanding of the complex role played by astrocytes within the central nervous system, and identify Kidins220 as a novel actor in the increasing number of pathologies characterized by astrocytic dysfunctions.