article published yes Aikaterini Stratigi author Miguel Soler-García author Mia Krout author Shikha Shukla author Mario De Bono author 4E3FF80E-F248-11E8-B48F-1D18A9856A870000-0001-8347-0443 Janet E. Richmond author Patrick Laurent author MaDe department A dynamic interplay between fast synaptic signals and slower neuromodulatory signals controls the excitatory/inhibitory (E/I) balance within neuronal circuits. The mechanisms by which neuropeptide signaling is regulated to maintain E/I balance remain uncertain. We designed a genetic screen to isolate genes involved in the peptidergic maintenance of the E/I balance in the C. elegans motor circuit. This screen identified the C. elegans orthologs of the presynaptic phosphoprotein synapsin (snn-1) and the protein phosphatase 1 (PP1) regulatory subunit PHACTR1 (phac-1). We demonstrate that both phac-1 and snn-1 alter the motor behavior of C. elegans, and genetic interactions suggest that SNN-1 contributes to PP1-PHAC-1 holoenzyme signaling. De novo variants of human PHACTR1, associated with early-onset epilepsies [developmental and epileptic encephalopathy 70 (DEE70)], when expressed in C. elegans resulted in constitutive PP1-PHAC-1 holoenzyme activity. Unregulated PP1-PHAC-1 signaling alters the synapsin and actin cytoskeleton and increases neuropeptide release by cholinergic motor neurons, which secondarily affects the presynaptic vesicle cycle. Together, these results clarify the dominant mechanisms of action of the DEE70 alleles and suggest that altered neuropeptide release may alter E/I balance in DEE70. https://research-explorer.ista.ac.at/download/19498/19525/2025_JourNeuroscience_Stratigi.pdf application/pdf2025-09-27no https://creativecommons.org/licenses/by/4.0/ Society for Neuroscience2025 eng 0270-6474 1529-2401 39919830 00146095270000110.1523/JNEUROSCI.1767-23.2024 4513 Stratigi A, Soler-García M, Krout M, et al. Neuroendocrine control of synaptic transmission by PHAC-1 in C. elegans. <i>Journal of Neuroscience</i>. 2025;45(13). doi:<a href="https://doi.org/10.1523/JNEUROSCI.1767-23.2024">10.1523/JNEUROSCI.1767-23.2024</a> A. Stratigi, M. Soler-García, M. Krout, S. Shukla, M. de Bono, J.E. Richmond, P. Laurent, Journal of Neuroscience 45 (2025). A. Stratigi <i>et al.</i>, “Neuroendocrine control of synaptic transmission by PHAC-1 in C. elegans,” <i>Journal of Neuroscience</i>, vol. 45, no. 13. Society for Neuroscience, 2025. Stratigi, Aikaterini, Miguel Soler-García, Mia Krout, Shikha Shukla, Mario de Bono, Janet E. Richmond, and Patrick Laurent. “Neuroendocrine Control of Synaptic Transmission by PHAC-1 in C. Elegans.” <i>Journal of Neuroscience</i>. Society for Neuroscience, 2025. <a href="https://doi.org/10.1523/JNEUROSCI.1767-23.2024">https://doi.org/10.1523/JNEUROSCI.1767-23.2024</a>. Stratigi A, Soler-García M, Krout M, Shukla S, de Bono M, Richmond JE, Laurent P. 2025. Neuroendocrine control of synaptic transmission by PHAC-1 in C. elegans. Journal of Neuroscience. 45(13), e1767232024. Stratigi, A., Soler-García, M., Krout, M., Shukla, S., de Bono, M., Richmond, J. E., &#38; Laurent, P. (2025). Neuroendocrine control of synaptic transmission by PHAC-1 in C. elegans. <i>Journal of Neuroscience</i>. Society for Neuroscience. <a href="https://doi.org/10.1523/JNEUROSCI.1767-23.2024">https://doi.org/10.1523/JNEUROSCI.1767-23.2024</a> Stratigi, Aikaterini, et al. “Neuroendocrine Control of Synaptic Transmission by PHAC-1 in C. Elegans.” <i>Journal of Neuroscience</i>, vol. 45, no. 13, e1767232024, Society for Neuroscience, 2025, doi:<a href="https://doi.org/10.1523/JNEUROSCI.1767-23.2024">10.1523/JNEUROSCI.1767-23.2024</a>. 194982025-04-06T22:01:32Z2025-09-30T11:29:28Z