Disrupting cortical astrocyte Ca²⁺ signaling in developing brain induces social deficits and depressive-like...

Astrocytes are present throughout the central nervous system and display complex intracellular Ca²⁺ signals. However, it is largely unknown regarding how astrocytic Ca²⁺ signals regulate neural microcircuits in developing brain and mammalian behavior in vivo. In this study, we specifically overexpressed the plasma membrane calcium-transporting ATPase2 (PMCA2) of cortical astrocytes and used immunohistochemistry, Ca²⁺ imaging, electrophysiology, and behavioral tests to investigate the effects of genetically reducing cortical astrocyte Ca²⁺ signaling during a critical developmental period in vivo. We found that reducing cortical astrocyte Ca²⁺ signaling during development led to social interaction deficits, depressive-like behaviors, and abnormal synaptic structure and transmission. In addition, restoring cortical astrocyte Ca²⁺ signaling using chemogenetic activation of Gq-coupled designer receptors exclusively activated by designer drugs rescued these synaptic and behavioral deficits. Together, our data demonstrate that the integrity of cortical astrocyte Ca²⁺ signaling in developing mice is critical for neural circuit development and may be involved in the pathogenesis of developmental neuropsychiatric diseases, such as autism spectrum disorders and depression.