Neuroendocrine Control of Synaptic Transmission by PHAC-1 in <i>C. elegans</i>

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 <i>C. elegans</i> motor circuit. This screen identified the <i>C. elegans</i> orthologs of the presynaptic phosphoprotein synapsin (<i>snn-1</i>) and the protein phosphatase 1 (PP1) regulatory subunit PHACTR1 (<i>phac-1</i>). We demonstrate that both <i>phac-1</i> and <i>snn-1</i> alter the motor behavior of <i>C. elegans</i>, 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 <i>C. elegans</i> 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.