Ascaris suum Informs Extrasynaptic Volume Transmission in Nematodes

Area of Science:

• Neurobiology
• Nematology
• Molecular Biology

Background:

• Nervous system function relies on synaptic connections, but nonsynaptic communication routes like extrasynaptic volume transmission (EVT) exist in invertebrates.
• While EVT is recognized in *Caenorhabditis elegans*, the role of body cavity fluid (pseudocoelomic fluid; PCF) in transmitting signaling molecules remains experimentally unverified.
• In *Ascaris suum*, FMRFamide-like peptides (FLPs) are implicated in reproductive organ stimulation, despite lacking direct synaptic connections.

Purpose of the Study:

• To investigate nonsynaptic neuropeptide signaling mediated by body cavity fluid in nematodes.
• To determine if *Ascaris suum* pseudocoelomic fluid (As-PCF) contains and transmits active neuropeptides.
• To explore the functional relevance of As-PCF and its components in both *A. suum* and *C. elegans*.

Main Methods:

• Analysis of neuropeptide content in *A. suum* PCF using peptidomics.
• *Ex vivo* bioassays using *A. suum* reproductive muscles to assess As-PCF activity.
• Functional assays using *C. elegans* to test As-PCF effects on FLP-18 receptors (NPR-4, -5) and behavior.
• Phylogenetic analysis of FLP-18 and its receptors across nematode species.

Main Results:

• *A. suum* PCF contains a diverse range of neuropeptides, with As-FLP-18A being the most abundant.
• As-PCF significantly modulates nematode reproductive muscle function, similar to synthetic FLP-18 peptides.
• As-PCF activates *C. elegans* FLP-18 receptors (NPR-4, -5) and induces behavioral changes.
• FLP-18 peptides and their receptors are conserved across the nematode phylum.

Conclusions:

• This study provides the first direct experimental evidence for extrasynaptic volume transmission of neuropeptides via PCF in nematodes.
• Nonsynaptic signaling is an integral component of the nematode functional connectome.
• Findings are relevant for receptor deorphanization and the development of novel therapeutic strategies against nematode pathogens.