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Resources » Paper

Takayanagi-Kiya, Seika et al. (2015) International Worm Meeting "A novel mutation in the ligand-gated ion channel lgc-46 affects excitation-inhibition imbalance in the C. elegans locomotor circuit."

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    Status:
    Publication type:
    Meeting_abstract
    WormBase ID:
    WBPaper00048091

    Takayanagi-Kiya, Seika, Cherra, Salvatore, Qi, Yingchuan B., & Jin, Yishi (2015). A novel mutation in the ligand-gated ion channel lgc-46 affects excitation-inhibition imbalance in the C. elegans locomotor circuit presented in International Worm Meeting. Unpublished information; cite only with author permission.

    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.

    Affiliations:
    - Division of Biological Sciences, Section of Neurobiology, Howard Hughes Medical Institute, University of California San Diego, La Jolla, CA, USA
    - Institute of Developmental and Regenerative Biology, Hangzhou Normal University, Hangzhou, China


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