Sinusoidal locomotion of C. elegans requires coordinated activity of excitatory and inhibitory motor neurons. The ACR-2 acetylcholine receptor is expressed in the cholinergic motor neurons, and an
acr-2(gf) mutation disrupts locomotion and causes spontaneous convulsion behavior (Jospin et al. 2009).
acr-2(gf) mutants display over-excitation of the cholinergic motor neurons accompanied by decreased activity of GABAergic motor neurons at the neuromuscular junctions, resulting in an imbalance in excitation (E) and inhibition (I) within the locomotor circuit. Interestingly, some human patients with Autosomal Dominant Nocturnal Frontal Lobe Epilepsy carry an identical missense mutation in the neuronal acetylcholine receptor beta2 subunit as in
acr-2(gf) (Marini & Guerrin, 2007). By analyzing a large number of genetic suppressors of
acr-2(gf), we have characterized several molecular pathways that modulate activity of the locomotor circuit. Here, we have identified a missense mutation in the pore-lining transmembrane domain of
lgc-46, which causes suppression of
acr-2(gf) convulsion. LGC-46 is a previously uncharacterized ligand-gated ion channel, closely related to the ACC ACh-gated chloride channel subfamily.
lgc-46(
ju825) behaves as a gain-of-function mutation, as
lgc-46(null) does not show effects on
acr-2(gf) convulsion.
lgc-46 is expressed in the nervous system, and transgenic neuron-specific expression studies support that
lgc-46 function is required in cholinergic neurons. Pharmacological analysis suggests that
lgc-46(
ju825) affects cholinergic release at the neuromuscular junction. We are currently determining the channel activity of LGC-46 and its functional interaction with the ACR-2 receptor. Our findings will lead to a further understanding of the regulation of E/I imbalance, and thus help conceptual advance in the treatments for human diseases caused by the impairment of neuronal activity.Ref: Jospin et al. 2009. PLoS Biol. 7(12):
e1000265.; Marini and Guerrin 2007. Biochem. Pharmacol. 74:1308-1314.; Stawicki, Takayanagi-Kiya et al. 2013. PLoS Genet. 9(5):
e1003472.