ASTROCYTE STORE-RELEASED CALCIUM MODULATES CORTICAL SYNAPSE DEVELOPMENT AND CIRCUIT FUNCTION

Astrocytes, a major class of glial cells, are critical regulators of synapse development during early postnatal life. While dysregulation of this process is implicated in numerous neurological disorders, the precise mechanisms by which astrocytes guide synapse formation and maturation remain poorly understood. A central signaling pathway for astrocytes is through fluctuation of intracellular calcium (Ca²⁺), which can arise from various sources and modulate a wide range of downstream effects. A key astrocytic mechanism for integrating neuronal signals is the release of Ca²⁺ from endoplasmic reticulum stores mediated by the IP₃ Receptor Type 2 (IP₃R2). Although defects in this signaling pathway have been mainly linked to adult brain dysfunction, its role in shaping synaptic development, a period when astrocyte-neuronal communication is established, is largely unknown. Here, we investigated the role of IP₃R2-mediated Ca²⁺ signaling in astrocyte-dependent regulation of synapse development in the mouse visual cortex. Using a combination of histological, molecular, and circuit-level approaches, we found that loss of astrocytic IP₃R2 leads to significant deficits in the maturation of glutamatergic but not GABAergic synapses. These synaptic disruptions were accompanied by attenuated visually evoked neuronal activation and impaired behavioral responses to visual threat stimuli. We further show that astrocytic morphological complexity is diminished in the absence of IP₃R2, suggesting that store-released Ca²⁺ is required for both the structural and functional maturation of astrocyte-neuron interactions. Our findings establish a critical role for astrocytic IP₃R2-mediated Ca²⁺ signaling in shaping excitatory circuit development and the emergence of visually driven behaviors.