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Neuron. 2018 Sep 19;99(6):1170-1187.e9. doi: 10.1016/j.neuron.2018.08.015. Epub 2018 Aug 30.

Reducing Astrocyte Calcium Signaling In Vivo Alters Striatal Microcircuits and Causes Repetitive Behavior.

Author information

1
Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA.
2
Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA.
3
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA; Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA; West Los Angeles VA Medical Center, Los Angeles, CA 90073, USA.
4
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA; Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA; Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA.
5
Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA; Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1751, USA. Electronic address: bkhakh@mednet.ucla.edu.

Abstract

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 two-photon laser scanning microscopy, electrophysiology, MINIscopes, RNA-seq, and a genetic approach to explore 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 facilitated 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 mouse obsessive-compulsive-like behavior.

PMID:
30174118
PMCID:
PMC6450394
[Available on 2019-09-19]
DOI:
10.1016/j.neuron.2018.08.015

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