Reducing astrocyte calcium signaling in vivo alters striatal microcircuits and causes repetitive behavior I

Astrocytes tile the central nervous system, but their functions in neural microcircuits in vivo and their roles in mammalian behavior remain incompletely defined. We used 2-photon laser scanning microscopy (2PLSM), electrophysiology, MINIscopes, RNA-seq and a new genetic approach to characterize the effects of reduced striatal astrocyte Ca2+ signaling in vivo. In wild type mice, reducing striatal astrocyte Ca2+-dependent signaling increased repetitive self-grooming behaviors by altering medium spiny neuron (MSN) activity. The mechanism involved astrocyte-mediated neuromodulation mediated by ambient GABA and was corrected by blocking astrocyte GABA transporter 3 (GAT-3). Furthermore, in a mouse model of Huntington’s disease, dysregulation of GABA and astrocyte Ca2+ signaling accompanied excessive self-grooming, which was relieved by blocking GAT-3. Assessments with RNA-seq revealed astrocyte genes and pathways regulated by Ca2+ signaling in a cell autonomous and non-cell autonomous manner, including Rab11a, a regulator of GAT-3 functional expression. Thus, striatal astrocytes contribute to neuromodulation controlling obsessive-compulsive-like behavior in mice. Total 16 samples were used in this data set. Whole striata were extraced from 8 adult mice: 4 mice received RiboTag AAV and AAV encoding a control protein and 4 mice received RiboTag AAV and AAV encoding a protein that suppresses calcium signals named hPMCA2w/b. After homogenization, RNA was purified from (i) cleared lysate as the input and control, and (ii) astrocyte-specific ribosome-associated RNA precipitated via a hemagglutinin (HA) tag.