Disrupting cortical astrocyte Ca signaling in developing brain induces social deficits and depressive-like behaviors.

Astrocytes are present throughout the central nervous system and display complex intracellular Ca signals. However, it is largely unknown regarding how astrocytic Ca 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, Ca imaging, electrophysiology, and behavioral tests to investigate the effects of genetically reducing cortical astrocyte Ca signaling during a critical developmental period in vivo. We found that reducing cortical astrocyte Ca signaling during development led to social interaction deficits, depressive-like behaviors, and abnormal synaptic structure and transmission. In addition, restoring cortical astrocyte Ca 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 Ca 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.