Reduced high-frequency motor neuron firing, EMG fractionation, and gait variability in awake walking ALS mice

Significance First recordings from awake walking symptomatic-stage amyotrophic lateral sclerosis (ALS) and control mice were made simultaneously from spinal cord motor pools and corresponding hindlimb flexor and extensor muscles. Spinal recordings revealed loss of high-frequency firing in ALS mice, and EMG showed an abnormal fractionated character with step-to-step variability and flexor/extensor coactivation, associated with step-to-step variability in kinematics and likely compensatory mechanisms that allow continued ability to walk in the face of motor neuron loss. 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.