Disrupting cortical astrocyte Ca²⁺ signaling in developing brain induces social deficits and depressive‐like behaviors

Abstract

Astrocytes are present throughout the central nervous system and display complex intracellular Ca 2+ signals. However, it is largely unknown regarding how astrocytic Ca 2+ signals regulate neural microcircuits in developing brain and mammalian behavior in vivo. In this study, we specifically overexpressed the plasma membrane calciumtransporting ATPase2 (PMCA2) of cortical astrocytes and used immunohistochemistry, Ca 2+ imaging, electrophysiology, and behavioral tests to investigate the effects of genetically reducing cortical astrocyte Ca 2+ signaling during a critical developmental period in vivo. We found that reducing cortical astrocyte Ca 2+ signaling during development led to social interaction deficits, depressive-like behaviors, and abnormal synaptic structure and transmission. In addition, restoring cortical astrocyte Ca 2+ 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 2+ 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.

Diurnal proteome profile of the mouse cerebral cortex: Conditional deletion of the Bmal1 circadian clock gene elevates astrocyte protein levels and cell abundance in the neocortex and hippocampus

“…On the contrary, the general picture in humans diagnosed with major depressive disorder seems to be a reduction in astrocyte density in the cerebral cortex (Cobb et al, 2016;O'Leary et al, 2021;Rajkowska & Stockmeier, 2013), but astrocyte hypertrophy has also been reported (Torres-Platas et al, 2011); this points to the possibility that dysregulation rather than absolute levels of cortical astrocyte activity and density may induce a depressive phenotype. Recent data suggest that disruption of cortical astrocyte calcium-signaling induces a depressive-like behavior accompanied by synaptic structure abnormalities in mice (Luo et al, 2023), which may be part of the mechanistic explanation linking astrocytes to depression. Another CKO mouse model, generated by use of a Cre-construct driven by the CamKII-promoter to knock out Bmal1 in all regions of the forebrain, while cellularly limiting the deletion to excitatory neurons, did not exhibit any affective symptoms (Snider et al, 2016).…”