TY - JOUR T1 - Enhancing GABAergic transmission improves locomotion in a <em>C. elegans</em> model of Spinal Muscular Atrophy JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0289-18.2018 SP - ENEURO.0289-18.2018 AU - Chia-Yen Wu AU - David A. Gagnon AU - Juliette S. Sardin AU - Urva Barot AU - Alex Telenson AU - Paulo E. Arratia AU - Robert G. Kalb Y1 - 2018/11/16 UR - http://www.eneuro.org/content/early/2018/11/16/ENEURO.0289-18.2018.abstract N2 - Spinal Muscular Atrophy (SMA) is a neuromuscular disease characterized by degeneration of spinal motor neurons resulting in variable degrees of muscular wasting and weakness. It is caused by a loss-of-function mutation in the Survival Motor Neuron (SMN1) gene. Caenorhabditis elegans (C. elegans) mutants lacking SMN recapitulate several aspects of the disease including impaired movement and shorted life span. We examined whether genes previously implicated in life span extension conferred benefits to C. elegans lacking SMN. We find that reducing DAF-2/insulin receptor signaling activity promotes survival and improves locomotor behavior in this C. elegans model of SMA. The locomotor dysfunction in C. elegans lacking SMN correlated with structural and functional abnormalities in GABAergic neuromuscular junctions. Moreover, we demonstrated that reduction in DAF-2 signaling reversed these abnormalities. Remarkably, enhancing GABAergic neurotransmission alone was able to correct the locomotor dysfunction. Our work indicated that an imbalance of excitatory/inhibitory activity within motor circuits and underlies motor system dysfunction in this SMA model. Interventions aimed at restoring the balance of excitatory/inhibitory activity in motor circuits could be of benefit to individuals with SMA.Significance Statement SMA is a pediatric motor neuron disease resulting from the loss of the SMN protein. While great effort has been expended on interventions aimed at increasing levels of compensatory SMN1, identification of genes that modify the SMA phenotype has lagged. Here we undertook a targeted genetic screen to identify SMA disease suppressors. We demonstrated that reduced insulin/insulin-like signaling is beneficial for not only longevity but also locomotor activity in SMA worm models. Our results from anatomical, functional, and genetic studies show that the impairment of GABAergic neurotransmission contributes to locomotor dysfunction in smn-1 null worms. Enhancing GABAergic neurotransmission alone can correct the locomotor dysfunction. This work leads to new understanding of disease pathogenesis and opens up new opportunities for therapy. ER -