Neuroendocrine control of synaptic transmission by PHAC-1 in C. elegans.

Abstract

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 (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.Significance Statement Alterations of the excitatory-inhibitory (E/I) balance within neuronal circuits contribute to seizures. Early-onset epilepsies are associated with 4 variants of human PHACTR1 (called DEE70). In a genetic screen designed to isolate genes involved in the maintenance of the E/I balance by peptidergic neuromodulators, we identified the C. elegans orthologs of PHACTR1 and of Synapsin. When introduced in C. elegans, the DEE70-associated variants reduced the E/I balance in motor circuits. Our results suggest that DEE70 variants induce the constitutive activity of an holophosphatase formed by PHACTR1. The constitutive holophosphatase signaling alters the Synapsin and Actin cytoskeleton and increases neuropeptide release which secondarily decreases E/I balance in circuits.