title: Astrocyte Ca2+Influx Negatively Regulates Neuronal Activity.
abstract: Maintenance of neural circuit activity requires appropriate regulation of excitatory and inhibitory synaptic transmission. Recently, glia have emerged as key partners in the modulation of neuronal excitability; however, the mechanisms by which glia regulate neuronal signaling are still being elucidated. Here, we describe an analysis of how Ca2+signals withinDrosophilaastrocyte-like glia regulate excitability in the nervous system. We find thatDrosophilaastrocytes exhibit robust Ca2+oscillatory activity manifested by fast, recurrent microdomain Ca2+fluctuations within processes that infiltrate the synaptic neuropil. Unlike the enhanced neuronal activity and behavioral seizures that were previously observed during manipulations that trigger Ca2+influx intoDrosophilacortex glia, we find that acute induction of astrocyte Ca2+influx leads to a rapid onset of behavioral paralysis and a suppression of neuronal activity. We observe that Ca2+influx triggers rapid endocytosis of the GABA transporter (GAT) from astrocyte plasma membranes, suggesting that increased synaptic GABA levels contribute to the neuronal silencing and paralysis. We identify Rab11 as a novel regulator of GAT trafficking that is required for this form of activity regulation. Suppression of Rab11 function strongly offsets the reduction of neuronal activity caused by acute astrocyte Ca2+influx, likely by inhibiting GAT endocytosis. Our data provide new insights into astrocyte Ca2+signaling and indicate that distinct glial subtypes in theDrosophilabrain can mediate opposing effects on neuronal excitability.
authors.affiliation: The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Yao V
authors.identifier: 0000-0001-7463-977X
authors.initials: YV
authors.lastname: Zhang
authors.affiliation: The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Kiel G
authors.initials: KG
authors.lastname: Ormerod
authors.affiliation: The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: J Troy
authors.identifier: 0000-0001-5576-2887
authors.initials: JT
authors.lastname: Littleton
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002413:Cations, Divalent / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D007473:Ion Channels; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010243:Paralysis / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D002118:Calcium; D002413:Cations, Divalent; D029721:Drosophila Proteins; D050485:GABA Plasma Membrane Transport Proteins; D007473:Ion Channels; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D005680:gamma-Aminobutyric Acid; D020691:rab GTP-Binding Proteins; C475684:TrpA1 protein, Drosophila; C559123:Rab11 protein, Drosophila; D000099193:rab11 GTP-Binding Proteins
keywords: Ca2+; Drosophila; GABA; GAT; Rab11; astrocyte