Reducing Excess Firing of Motor Neurons Delays Symptoms in Animal Model of ALS

Reducing the excess firing of motor neurons in an animal model of amyotrophic lateral sclerosis (ALS) prevents the death of nerve cells and significantly delays the onset of motor symptoms, a recent study has found.

Because the scientific approach made use of two techniques that have been studied extensively in humans, researchers are cautiously optimistic it may provide a potential treatment for people with ALS.

The study, “Cortical interneuron-mediated inhibition delays the onset of amyotrophic lateral sclerosis,” was published in the journal Brain.

To send messages throughout the body, neurons need to transmit signals to communicate with one another. “This communication can be either excitatory or inhibitory,” study co-author Melanie Woodin, PhD, a professor at the University of Toronto, said in a press release.

“Excitation is like the gas pedal in your car and inhibition is the brake pedal. Too much gas and you’ll speed off the road; too much brake and you don’t go anywhere. So, to drive properly, you need a balance between the two,” she said.

In healthy people, a balance between excitatory and inhibitory signals is what ensures a normal functioning of the brain. But in some people, this balance is lost, and nerve cells start firing much more than they should.

This phenomenon, called hyperexcitability, is common in the region of the brain that is mostly affected in ALS patients (the motor cortex, which controls movement) and is what causes symptoms such as involuntary muscle contractions, cramps, excessive reflexes, and muscle stiffness (spasticity).

In these patients, the excess neuronal firing is believed to happen because a set of inhibitory cells in the motor cortex, called parvalbumin-positive interneurons, have a much lower activity than in healthy brains.

The team set out to explore whether increasing the activity of these interneurons could reduce hyperexcitability in the motor cortex, and improve disease symptoms, in an animal model of ALS.

The researchers took advantage of a revolutionary technique in neuroscience called chemogenetics, in which a large molecule, such as a receptor, is modified in a way that is active only when bound to a small compound. This allows investigators to adjust the activation of the receptor in specific nerve cells while minimizing the side effects of treatment.

In their study, the receptor was directed only at the interneurons present in the motor cortex, and was activated with a small molecule called clozapine-N-oxide (CNO) — though an approved antipsychotic medication clozapine also can activate this receptor.

Researchers first used mouse models of ALS — carrying a mutation in the SOD1 gene — that were genetically modified to carry this engineered receptor. In these animals, treatment with CNO before symptoms were evident significantly delayed motor symptoms, including loss of forelimb and hindlimb function, balance, and motor coordination, compared to animals receiving CNO but lacking the receptor.

Molecularly, the team found that the activation of these inhibitory interneurons was preserving the health of nerve cells overall, and preventing the death of motor neurons, compared to untreated ALS mice.

The results were replicated when the receptor was delivered to animals using a viral vector, either before symptoms appeared or at symptom onset, which more closely resembles approaches used to treat patients.

In animals treated when their symptoms became evident, activation of inhibitory interneurons not only delayed the onset of motor deficits, but also helped mice slowly gain weight, ultimately extending their survival.

Overall, the findings suggested that hyperexcitability in the motor cortex may be driving the onset and progression of ALS symptoms, and that preventing this excess motor firing may be a way of treating ALS.

“This advancement in decreasing cortical hyperexcitability has the potential to have a major impact on treating ALS in humans,” said Lorne Zinman, MD, also a professor at the University of Toronto. “Much more work is needed but this advance shows great promise toward a path to stopping this disease.”

“Excessive activity of the upper motor neurons could be an important contributor to the disease and Professor Woodin’s work focused on a novel way to stimulate neighboring neurons that can put the brakes on this abnormal biology,” said David Taylor, PhD, vice president of research at ALS Canada.

“Her results in ALS model mice are exciting and hopefully this can someday be a treatment strategy tested in human clinical trials,” he concluded.