Enhanced motor cortex output and disinhibition in asymptomatic female mice with C9orf72 genetic expansion
Sona Amalyan,
Suhel Tamboli,
Ivan Lazarevich,
Dimitry Topolnik,
Leandra Harriet Bouman,
Lisa Topolnik
Affiliations
Sona Amalyan
Department of Biochemistry, Microbiology and Bio-informatics, Laval University, Québec, QC, Canada; Neuroscience Axis, CHU de Québec Research Center (CHUL), Québec, QC, Canada
Suhel Tamboli
Department of Biochemistry, Microbiology and Bio-informatics, Laval University, Québec, QC, Canada; Neuroscience Axis, CHU de Québec Research Center (CHUL), Québec, QC, Canada
Ivan Lazarevich
École Normale Supérieure, Laboratoire de Neurosciences Cognitives, Group for Neural Theory, Paris, France
Dimitry Topolnik
Department of Biochemistry, Microbiology and Bio-informatics, Laval University, Québec, QC, Canada; Neuroscience Axis, CHU de Québec Research Center (CHUL), Québec, QC, Canada
Leandra Harriet Bouman
Department of Biochemistry, Microbiology and Bio-informatics, Laval University, Québec, QC, Canada; Neuroscience Axis, CHU de Québec Research Center (CHUL), Québec, QC, Canada
Lisa Topolnik
Department of Biochemistry, Microbiology and Bio-informatics, Laval University, Québec, QC, Canada; Neuroscience Axis, CHU de Québec Research Center (CHUL), Québec, QC, Canada; Corresponding author
Summary: Information and action coding by cortical circuits relies on a balanced dialogue between excitation and inhibition. Circuit hyperexcitability is considered a potential pathophysiological mechanism in various brain disorders, but the underlying deficits, especially at early disease stages, remain largely unknown. We report that asymptomatic female mice carrying the chromosome 9 open reading frame 72 (C9orf72) repeat expansion, which represents a high-prevalence genetic abnormality for human amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) spectrum disorder, exhibit abnormal motor cortex output. The number of primary motor cortex (M1) layer 5 pyramidal neurons is reduced in asymptomatic mice, with the surviving neurons receiving a decreased inhibitory drive that results in a higher M1 output, specifically during high-speed animal locomotion. Importantly, using deep-learning algorithms revealed that speed-dependent M1 output predicts the likelihood of C9orf72 genetic expansion. Our data link early circuit abnormalities with a gene mutation in asymptomatic ALS/FTLD carriers.
