title: Glial Expression of the Caenorhabditis elegans Gene swip-10 Supports Glutamate Dependent Control of Extrasynaptic Dopamine Signaling.
abstract: Glial cells play a critical role in shaping neuronal development, structure, and function. In a screen for Caenorhabditis elegans mutants that display dopamine (DA)-dependent, Swimming-Induced Paralysis (Swip), we identified a novel gene, swip-10, the expression of which in glia is required to support normal swimming behavior. swip-10 mutants display reduced locomotion rates on plates, consistent with our findings of elevated rates of presynaptic DA vesicle fusion using fluorescence recovery after photobleaching. In addition, swip-10 mutants exhibit elevated DA neuron excitability upon contact with food, as detected by in vivo Ca(2+) monitoring, that can be rescued by glial expression of swip-10. Mammalian glia exert powerful control of neuronal excitability via transporter-dependent buffering of extracellular glutamate (Glu). Consistent with this idea, swip-10 paralysis was blunted in mutants deficient in either vesicular Glu release or Glu receptor expression and could be phenocopied by mutations that disrupt the function of plasma membrane Glu transporters, most noticeably glt-1, the ortholog of mammalian astrocytic GLT1 (EAAT2). swip-10 encodes a protein containing a highly conserved metallo-β-lactamase domain, within which our swip-10 mutations are located and where engineered mutations disrupt Swip rescue. Sequence alignments identify the CNS-expressed gene MBLAC1 as a putative mammalian ortholog. Together, our studies provide evidence of a novel pathway in glial cells regulated by swip-10 that limits DA neuron excitability, DA secretion, and DA-dependent behaviors through modulation of Glu signaling.
authors.affiliation: Department of Pharmacology.
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Hardaway
authors.affiliation: Department of Pharmacology.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Sturgeon
authors.affiliation: Department of Pharmacology.
authors.forename: Chelsea L
authors.initials: CL
authors.lastname: Snarrenberg
authors.affiliation: Life Sciences Institute and Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Zhaoyu
authors.initials: Z
authors.lastname: Li
authors.affiliation: Life Sciences Institute and Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: X Z Shawn
authors.initials: XZ
authors.lastname: Xu
authors.affiliation: Department of Pharmacology.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Bermingham
authors.affiliation: Fisk University, Nashville, Tennessee 37208, and.
authors.forename: Peace
authors.initials: P
authors.lastname: Odiase
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
authors.forename: W Clay
authors.initials: WC
authors.lastname: Spencer
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
authors.forename: David M
authors.initials: DM
authors.lastname: Miller
authors.affiliation: University of North Dakota School of Medicine and Health Sciences, Department of Basic Sciences, Grand Forks, North Dakota 58202.
authors.forename: Lucia
authors.identifier: http://orcid.org/0000-0001-8754-3777
authors.initials: L
authors.lastname: Carvelli
authors.affiliation: Department of Pharmacology.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Hardie
authors.affiliation: Department of Pharmacology, Department of Psychiatry, and randy.blakely@vanderbilt.edu.
authors.forename: Randy D
authors.initials: RD
authors.lastname: Blakely
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D018613:Microscopy, Confocal; D009043:Motor Activity / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D029742:Caenorhabditis elegans Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C000601014:SWIP-10 protein, C elegans; D018698:Glutamic Acid; D004298:Dopamine
keywords: C. elegans; dopamine; glia; glutamate; transporters