Cortical interneuron-mediated inhibition delays the onset of amyotrophic lateral sclerosis

Brain. 2020 Mar 1;143(3):800-810. doi: 10.1093/brain/awaa034.


Amyotrophic lateral sclerosis is a fatal disease resulting from motor neuron degeneration in the cortex and spinal cord. Cortical hyperexcitability is a hallmark feature of amyotrophic lateral sclerosis and is accompanied by decreased intracortical inhibition. Using electrophysiological patch-clamp recordings, we revealed parvalbumin interneurons to be hypoactive in the late pre-symptomatic SOD1*G93A mouse model of amyotrophic lateral sclerosis. We discovered that using adeno-associated virus-mediated delivery of chemogenetic technology targeted to increase the activity of the interneurons within layer 5 of the primary motor cortex, we were able to rescue intracortical inhibition and reduce pyramidal neuron hyperexcitability. Increasing the activity of interneurons in the layer 5 of the primary motor cortex was effective in delaying the onset of amyotrophic lateral sclerosis-associated motor deficits, slowing symptom progression, preserving neuronal populations, and increasing the lifespan of SOD1*G93A mice. Taken together, this study provides novel insights into the pathogenesis and treatment of amyotrophic lateral sclerosis.

Keywords: amyotrophic lateral sclerosis; chemogenetics; inhibitory synaptic transmission; parvalbumin; primary motor cortex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae
  • Amyotrophic Lateral Sclerosis / physiopathology*
  • Animals
  • Disease Progression
  • Female
  • Interneurons / physiology*
  • Male
  • Mice
  • Mice, Transgenic
  • Motor Cortex / physiology*
  • Motor Skills / physiology
  • Neural Inhibition / physiology*
  • Patch-Clamp Techniques
  • Pyramidal Cells / physiology
  • Superoxide Dismutase-1 / genetics
  • Transfection


  • Sod1 protein, mouse
  • Superoxide Dismutase-1