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J Neurosci. 2015 Jun 24;35(25):9409-23. doi: 10.1523/JNEUROSCI.0800-15.2015.

Glial Expression of the Caenorhabditis elegans Gene swip-10 Supports Glutamate Dependent Control of Extrasynaptic Dopamine Signaling.

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Department of Pharmacology.
Life Sciences Institute and Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109.
Fisk University, Nashville, Tennessee 37208, and.
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
University of North Dakota School of Medicine and Health Sciences, Department of Basic Sciences, Grand Forks, North Dakota 58202.
Department of Pharmacology, Department of Psychiatry, and


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.


C. elegans; dopamine; glia; glutamate; transporters

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