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TitleCortical interneuron-mediated inhibition delays the onset of amyotrophic lateral sclerosis.
Publication TypeJournal Article
Year of Publication2020
AuthorsC Khademullah, Sahara, Afif J. Aqrabawi, Kara M. Place, Zahra Dargaei, Xinyi Liang, Jessica C. Pressey, Simon Bedard, Jy Wei Yang, Danielle Garand, Iason Keramidis, Alicja Gasecka, Daniel Côté, Yves De Koninck, Julia Keith, Lorne Zinman, Janice Robertson, Jun Chul Kim, and Melanie A. Woodin
JournalBrain
Volume143
Issue3
Pagination800-810
Date Published2020 03 01
ISSN1460-2156
KeywordsAdenoviridae, Amyotrophic Lateral Sclerosis, Animals, Disease Progression, Female, Interneurons, Male, Mice, Mice, Transgenic, Motor Cortex, Motor Skills, Neural Inhibition, Patch-Clamp Techniques, Pyramidal Cells, Superoxide Dismutase-1, Transfection
Abstract

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.

DOI10.1093/brain/awaa034
Alternate JournalBrain
PubMed ID32203578