Neuropeptides Function in a Homeostatic Manner to Modulate Excitation-Inhibition Imbalance in C. elegans

Neuropeptides play crucial roles in modulating neuronal networks,including changing intrinsic properties of neurons and synaptic efficacy. we previously reported a caenorhabditis elegans mutant,acr-2(gf),that displays spontaneous convulsions as the result of a gain-of-function mutation in a neuronal nicotinic acetylcholine receptor subunit. the acr-2 channel is expressed in the cholinergic motor neurons,and acr-2(gf) causes cholinergic overexcitation accompanied by reduced gabaergic inhibition in the locomotor circuit. here we show that neuropeptides play a homeostatic role that compensates for this excitation-inhibition imbalance in the locomotor circuit. loss of function in genes required for neuropeptide processing or release of dense core vesicles specifically modulate the convulsion frequency of acr-2(gf). the proprotein convertase egl-3 is required in the cholinergic motor neurons to restrain convulsions. electrophysiological recordings of neuromuscular junctions show that loss of egl-3 in acr-2(gf) causes a further reduction of gabaergic inhibition. we identify two neuropeptide encoding genes,flp-1 and flp-18,that together counteract the excitation-inhibition imbalance in acr-2(gf) mutants. we further find that acr-2(gf) causes an increased expression of flp-18 in the ventral cord cholinergic motor neurons and that overexpression of flp-18 reduces the convulsion of acr-2(gf) mutants. the effects of these peptides are in part mediated by two g-protein coupled receptors,npr-1 and npr-5. our data suggest that the chronic overexcitation of the cholinergic motor neurons imposed by acr-2(gf) leads to an increased production of fmrfamide neuropeptides,which act to decrease the activity level of the locomotor circuit,thereby homeostatically modulating the excitation and inhibition imbalance. © 2013 stawicki et al.