title: Neuropeptides function in a homeostatic manner to modulate excitation-inhibition imbalance in C. elegans.
abstract: 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.
authors: Division of Biological Sciences, Section of Neurobiology, University of California San Diego, La Jolla, California, United States of America.
authors: Tamara M
authors: TM
authors: Stawicki
authors: Seika
authors: S
authors: Takayanagi-Kiya
authors: Keming
authors: K
authors: Zhou
authors: Yishi
authors: Y
authors: Jin
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D059329:Cholinergic Neurons / Q000378:metabolism*; D055724:Electrophysiological Phenomena; D056966:Excitation Contraction Coupling / Q000502:physiology; D019835:FMRFamide / Q000378:metabolism; D006706:Homeostasis; D008297:Male; D009043:Motor Activity / Q000502:physiology; D009046:Motor Neurons / Q000378:metabolism / Q000502:physiology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D045706:Proprotein Convertase 2 / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000378:metabolism / Q000503:physiopathology
chemical_list: C098140:Acr-2 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D009479:Neuropeptides; D011978:Receptors, Nicotinic; D019835:FMRFamide; C473666:EGL-3 proprotein convertase, C elegans; D045706:Proprotein Convertase 2
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