Reduced high-frequency motor neuron firing, EMG fractionation, and gait variability in awake walking ALS mice.
Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease prominently featuring motor neuron (MN) loss and paralysis. A recent study using whole-cell patch clamp recording of MNs in acute spinal cord slices from symptomatic adult ALS mice showed that the fastest firing MNs are preferentially lost. To measure the in vivo effects of such loss, awake symptomatic-stage ALS mice performing self-initiated walking on a wheel were studied. Both single-unit extracellular recordings within spinal cord MN pools for lower leg flexor and extensor muscles and the electromyograms (EMGs) of the corresponding muscles were recorded. In the ALS mice, we observed absent or truncated high-frequency firing of MNs at the appropriate time in the step cycle and step-to-step variability of the EMG, as well as flexor-extensor coactivation. In turn, kinematic analysis of walking showed step-to-step variability of gait. At the MN level, the higher frequencies absent from recordings from mutant mice corresponded with the upper range of frequencies observed for fast-firing MNs in earlier slice measurements. These results suggest that, in SOD1-linked ALS mice, symptoms are a product of abnormal MN firing due at least in part to loss of neurons that fire at high frequency, associated with altered EMG patterns and hindlimb kinematics during gait.
Interdepartmental Program in Neuroscience, Yale University School of Medicine, New Haven, CT 06510.
Muhamed
M
Hadzipasic
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510.|Department of Genetics, Yale University School of Medicine, New Haven, CT 06510.
Weiming
W
Ni
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510.|Department of Genetics, Yale University School of Medicine, New Haven, CT 06510.
Maria
M
Nagy
Sackler Institute Summer Scholar Program, Yale University School of Medicine, New Haven, CT 06510.
Natalie
N
Steenrod
Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510.
Matthew J
MJ
McGinley
Sackler Institute Summer Scholar Program, Yale University School of Medicine, New Haven, CT 06510.
Adi
A
Kaushal
Interdepartmental Program in Neuroscience, Yale University School of Medicine, New Haven, CT 06510.
Eleanor
E
Thomas
Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510.|Kavli Institute of Neuroscience, Yale University School of Medicine, New Haven, CT 06510.
David A
DA
McCormick
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510; arthur.horwich@yale.edu.|Department of Genetics, Yale University School of Medicine, New Haven, CT 06510.|Kavli Institute of Neuroscience, Yale University School of Medicine, New Haven, CT 06510.
Arthur L
0000-0001-9561-8839
AL
Horwich
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D001696:Biomechanical Phenomena; D004195:Disease Models, Animal; D004576:Electromyography; D005684:Gait / Q000502:physiology*; D006614:Hindlimb / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000502:physiology*; D018482:Muscle, Skeletal / Q000294:innervation / Q000503:physiopathology; D009154:Mutation; D000072105:Superoxide Dismutase-1 / Q000235:genetics*
C000606291:Sod1 protein, mouse; D000072105:Superoxide Dismutase-1
ALS; EMG; MN firing; in vivo recording; kinematics