Gary Armstrong, a scientist at The Neuro, is helping solve one of the mysteries that have made amyotrophic lateral sclerosis (ALS) such a challenging subject of research and treatment.
ALS is a neurodegenerative disease in which motor neurons progressively die, causing total paralysis and death. Much ALS research has been devoted to examining the spinal cord’s motor neurons and their connections with all the muscles in the body. I can type these words, for example, because my spinal cord’s motor neurons are transmitting signals to my fingers. These signals originate in the motor neurons in the brain, which, Armstrong notes, have received much less research attention.
“Motor neurons in the spinal cord, which coordinate muscle contractions, are widely studied in mice models. But dysfunction in the motor neurons in the brain itself is poorly understood,” says Armstrong. “One reason for this is that there were no good animal models to work on.”
Armstrong was able to create an informative ALS model by implanting glass electrodes into tiny zebrafish. The electrodes monitored the flow of signals from neurons in the brainstem to lower motor neurons in the spinal cord.
“We found something novel in the study of ALS: a duality in the strength of the signals,” says Armstrong. “In the spinal cord motor neurons, there were defects that weakened the neuronal junctions at the muscle. But in the neuronal signals that were coming down to the spinal cord motor neurons, the connectivity was stronger than usual.”
Stronger connectivity can lead to synapses firing in a highly excitatory mode as happens, for example, in certain epileptic seizures and following stroke where neurons are firing uncontrollably all at once. Epilepsy seizures usually last for only a few minutes. In ALS, the heightened excitatory action is much smaller so that the motor neurons can cope without a person going into convulsions. What is not clear is how motor neurons deal with these small excitatory actions over the course of many years.
“If the synaptic activity is too strong, it’s not good for motor neurons and probably participates in the neurons’ death,” says Armstrong. “When a motor neuron is depolarized, calcium ions begin to flow into the motor neuron. Calcium is very tightly regulated in neurons, and motor neurons are particularly vulnerable to high levels of calcium influx. Of course, motor neurons need a certain amount of calcium to perform normal biological functions.”
“Our research shows that this heightened activity is coming from synaptic inputs. It’s the first time this has been shown using physiological processes. This is a fundamental study into what is causing increased excitatory inputs in ALS.”
Controlling the amount of calcium entering the upper motor neurons might be a step toward finding an effective method of treating ALS, a disease that affects the lives of 3,000 Canadians as well as that of their families.
Their results were published in the journal Nature on June 24, 2019.