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

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 Ca signaling in vivo. In wild-type mice, reducing striatal astrocyte Ca-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 Ca signaling accompanied excessive self-grooming, which was relieved by blocking GAT-3. Assessments with RNA-seq revealed astrocyte genes and pathways regulated by Ca 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.

Questions and (some) answers on reactive astrocytes

“…Therefore, methods with cellular resolution like electrophysiology combined with fluorescent detection of markers, multidimensional cytometry, and two‐photon imaging with functional sensors are methods of choice to establish how specific types of reactive astrocytes function. Several elegant studies recently succeeded in providing new insight into the complexity of astrocyte functions in the normal brain (Bindocci et al, ; Chung et al, ; Martin, Bajo‐Graneras, Moratalla, Perea, & Araque, ; Nimmerjahn & Bergles, ) and in disease (Bardehle et al, ; Delekate et al, ; John Lin et al, ; Yu et al, ). Future studies will need to implement such refined methods in relevant disease models, to study reactive astrocyte responses at the single‐cell level.…”

“…Several elegant studies recently succeeded in providing new insight into the complexity of astrocyte functions in the normal brain (Bindocci et al, 2017;Chung et al, 2013;Martin, Bajo-Graneras, Moratalla, Perea, & Araque, 2015;Nimmerjahn & Bergles, 2015) and in disease (Bardehle et al, 2013;Delekate et al, 2014;John Lin et al, 2017;Yu et al, 2018). Future studies will need to implement such refined methods in relevant disease models, to study reactive astrocyte responses at the single-cell level.…”

Stress‐induced structural and functional modifications of astrocytes—Further implicating glia in the central response to stress

“…This will occur when current experts in the field begin to adopt these techniques or when glial‐focused researchers turn their attention to stress disorders. There are now multiple tools available to control the activity of astrocytes in a precise spatial and temporal manner; this includes the chemogenetic and optogenetic manipulation of astrocytic signaling (Adamsky et al, ; Agulhon et al, ; Jones, Paniccia, Lebonville, Reissner, & Lysle, ; Mederos et al, ; Wang et al, ), as well as a novel approach to decrease endogenous astrocyte calcium activity by expressing a human plasma membrane calcium pump, which extrudes calcium from the cell (Yu et al, ). The use of these tools will greatly facilitate studies designed to better understand the role of astrocytes in the initiation, development, maintenance, or progression of stress disorders.…”

Astrocytic striatal GABA transporter activity governs dopamine release and shows maladaptive downregulation in early parkinsonism

“…In addition, mRNA for GAT-1 and for has been found in midbrain DA neurons and these GATs have been suggested but not confirmed to be located on striatal DA axons to support GABA co-storage and co-release (Tritsch et al, 2014). Ambient GABA tone on SPNs in dorsal striatum is limited by the activity of GAT-1 and GAT-3 (Kirmse et al, 2008(Kirmse et al, , 2009Santhakumar et al, 2010;Wójtowicz et al, 2013), and recent evidence indicates that dysregulation of GAT-3 on striatal astrocytes results in profound changes to SPN activity and striatal-dependent behavior (Yu et al, 2018).…”

“…Tonic inhibition by ambient GABA across the mammalian brain is usually limited by uptake by plasma membrane GABA transporters (GATs) (Brickley and Mody, 2012). There are two isoforms of the GAT in striatum: GAT-1 (Slc6a1), abundant in axons of GABAergic neurons (Augood et al, 1995;Durkin et al, 1995;Ng et al, 2000;Yasumi et al, 1997); and GAT-3 (Slc6a11), expressed moderately (Ficková et al, 1999;Ng et al, 2000;Yasumi et al, 1997) but observed particularly on astrocytes (Chai et al, 2017;Ng et al, 2000;Yu et al, 2018). Emerging transcriptomic data additionally indicate that striatal astrocytes express both GAT-3 and GAT-1 (Chai et al, 2017;Gokce et al, 2016;Zhang et al, 2014).…”