Enhancing GABAergic Transmission Improves Locomotion in a<i>Caenorhabditis elegans</i>Model of Spinal Muscular Atrophy

Abstract

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 (<i>SMN1</i>) gene. <i>Caenorhabditis elegans</i> mutants lacking <i>SMN</i> 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 <i>C. elegans</i> lacking SMN. We find that reducing daf-2/insulin receptor signaling activity promotes survival and improves locomotor behavior in this <i>C. elegans</i> model of SMA. The locomotor dysfunction in <i>C. elegans</i> lacking <i>SMN</i> correlated with structural and functional abnormalities in GABAergic neuromuscular junctions (NMJs). Moreover, we demonstrated that reduction in <i>daf-2</i> 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.