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

Xinzhu Yu; Anna M W Taylor; Jun Nagai; Peyman Golshani; Christopher J Evans; Giovanni Coppola; Baljit S Khakh

doi:10.1016/j.neuron.2018.08.015

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

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

Authors

Xinzhu Yu¹, Anna M W Taylor², Jun Nagai¹, Peyman Golshani³, Christopher J Evans², Giovanni Coppola⁴, Baljit S Khakh⁵

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Astrocytes / metabolism*
Behavior, Animal / physiology*
Calcium / metabolism*
Calcium Signaling / physiology
Corpus Striatum / metabolism
GABA Plasma Membrane Transport Proteins / metabolism
Humans
Huntington Disease / genetics*
Mice, Transgenic
Neurons / physiology

Substances

GABA Plasma Membrane Transport Proteins
Calcium

Abstract

Publication types

MeSH terms

Substances

Grants and funding