Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results in the progressive loss of motor neurons, voluntary muscle control, and the eventual death of those it afflicts. Though only a small percentage of ALS cases have a (known) genetic basis, transgenic mice have been important for understanding the disease. In 2009, Arthur Horwich and his lab at Yale developed a mouse model expressing the human SOD1 gene, responsible for about 20% of inherited human cases, along with a fluorescent YFP tag for monitoring gene expression. Most mice of this strain will become paralyzed and die by six months of age. Yet up until only a few days before paralysis, the mice move about with seemingly little difficulty.

Identifying the underlying changes to peripheral neural network function in the SOD1 model has been the focus of lab member Muhamed Hadzipasic. In a previous in vitro study involving spinal cord slices, Hadzipasic broadly categorized four classes of motor neurons based on their firing speed and found that by four months, SOD1 mice will have lost all of the fastest spiking ones. The next step meant moving beyond tissue samples; his in vivo follow-up is reported in the Proceedings of the National Academy of Sciences (113, E7600–E7609; 2016).

Capturing movement was important to Hadzipasic because of the tangible connection between motor system output and motor neuron physiology. To record activity in awake, moving animals, he adapted and combined a head-fixed wheel platform with a spinal brace previously used for anesthetized imaging. With sugar water as a reward, the mice were trained to walk on the wheel while head- and lumbar spine-fixed, allowing high-speed video recording of gait as well as EMG and single-unit recordings of motor neurons.

Credit: GlobalIP/Getty

Though stride length was maintained over much of the course of disease progression, the high-speed video showed increases in gait variability. EMGs revealed highly fractionated, “choppy” signals and overlapping flexor and extensor muscle contractions. And single-cell recordings confirmed the in vitro observation that the fastest firing neurons are lost as the disease progresses, along with a lack of synchronization at the individual unit level.

Though exactly why the fast firing neurons die off first remains to be seen, both Hadzipasic and Horwich believe the results may point towards a broader understanding of motor system failure. According to Horwich, “We think ALS represents a multifaceted but common way that the motor system falls apart...if we can understand something about how it collapses, we might be able to generate some means to slow that down or even prevent it, regardless of what the primary triggering cause might be.”