Enhancing GABAergic Transmission Improves Locomotion in a Caenorhabditis elegans Model of Spinal Muscular Atrophy

eNeuro. 2019 Jan 2;5(6):ENEURO.0289-18.2018. doi: 10.1523/ENEURO.0289-18.2018. eCollection 2018 Nov-Dec.

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 (SMN1) gene. Caenorhabditis 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 (NMJs). 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.

Keywords: FOXO transcription factor; SMN protein; aging; neuromuscular junction; suppressor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adjuvants, Immunologic / pharmacology
  • Animals
  • Animals, Genetically Modified
  • Biomechanical Phenomena / drug effects
  • Biomechanical Phenomena / genetics
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism
  • Cholinesterase Inhibitors / pharmacology
  • Disease Models, Animal
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gait Disorders, Neurologic / etiology*
  • Gait Disorders, Neurologic / pathology
  • Gait Disorders, Neurologic / therapy*
  • Levamisole / pharmacology
  • Longevity / drug effects
  • Longevity / genetics
  • Muscular Atrophy, Spinal / complications*
  • Muscular Atrophy, Spinal / genetics
  • Muscular Atrophy, Spinal / therapy
  • Neuromuscular Junction / drug effects
  • Neuromuscular Junction / pathology
  • Pyridostigmine Bromide / pharmacology
  • RNA Interference / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Survival Analysis
  • Survival of Motor Neuron 1 Protein / genetics
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Adjuvants, Immunologic
  • Caenorhabditis elegans Proteins
  • Cholinesterase Inhibitors
  • Forkhead Transcription Factors
  • Survival of Motor Neuron 1 Protein
  • daf-16 protein, C elegans
  • smn-1 protein, C elegans
  • Levamisole
  • gamma-Aminobutyric Acid
  • Pyridostigmine Bromide