Ascaris suum informs extrasynaptic volume transmission in nematodes

Louise E. Atkinson, Yang Liu, Fiona McKay, Elke Vandewyer, Charles Viau, Allister Irvine, Bruce A. Rosa, Zihui Li, Qingxiao Liang, Nikki J. Marks, Aaron G. Maule, Makedonka Mitreva, Isabel Beets, Lingjun Li, Angela Mousley*

*Corresponding author for this work

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Neural circuit synaptic connectivities (the connectome) provide the anatomical foundation for our understanding of nematode nervous system function. However, other nonsynaptic routes of communication are known in invertebrates including extrasynaptic volume transmission (EVT), which enables short- and/or long-range communication in the absence of synaptic connections. Although EVT has been highlighted as a facet of Caenorhabditis elegans neurosignaling, no experimental evidence identifies body cavity fluid (pseudocoelomic fluid; PCF) as a vehicle for either neuropeptide or biogenic amine transmission. In the parasitic nematode Ascaris suum, FMRFamide-like peptides encoded on flp-18 potently stimulate female reproductive organs but are expressed in cells that are anatomically distant from the reproductive organ, with no known synaptic connections to this tissue. Here we investigate nonsynaptic neuropeptide signaling in nematodes mediated by the body cavity fluid. Our data show that (i) A. suum PCF (As-PCF) contains a catalog of neuropeptides including FMRFamide-like peptides and neuropeptide-like proteins, (ii) the A. suum FMRFamide-like peptide As-FLP-18A dominates the As-PCF peptidome, (iii) As-PCF potently modulates nematode reproductive muscle function ex vivo, mirroring the effects of synthetic FLP-18 peptides, (iv) As-PCF activates the C. elegans FLP-18 receptors NPR-4 and -5, (v) As-PCF alters C. elegans behavior, and (vi) FLP-18 and FLP-18 receptors display pan-phylum distribution in nematodes. This study provides the first direct experimental evidence to support an extrasynaptic volume route for neuropeptide transmission in nematodes. These data indicate nonsynaptic signaling within the nematode functional connectome and are particularly pertinent to receptor deorphanization approaches underpinning drug discovery programs for nematode pathogens.

Original languageEnglish
Pages (from-to)3176-3188
Number of pages13
JournalACS chemical neuroscience
Issue number17
Early online date04 Aug 2021
Publication statusPublished - 01 Sep 2021


  • Biochemistry
  • Cell Biology
  • Cognitive Neuroscience
  • General Medicine
  • Physiology


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