By Michelle Jaffee
New research reveals that a type of support cell in the spinal cord plays an important role in influencing plasticity of motor neurons responsible for breathing, a key insight that could help refine ongoing studies into a potential therapy for compromised breathing and other movements.
The experimental therapy, called acute intermittent hypoxia, involves delivering a lower level of oxygen in repeated short bursts. A potential treatment for impaired breathing or other movements in spinal cord injury, ALS, and multiple sclerosis, acute intermittent hypoxia is undergoing testing in translational studies from the lab to human clinical trials.
Now, McKnight Brain Institute researchers have shown that spinal microglia — immune cells of the central nervous system — regulate plasticity in respiratory motor neurons that is triggered by the experimental treatment. The findings of the rodent-model study were published Nov. 28 in the journal Nature Communications.
“This study demonstrates that plasticity in the phrenic motor neurons that innervate and contract the diaphragm exhibit plasticity, and that they participate in regulating their own plasticity following therapeutic acute intermittent hypoxia by interacting with nearby cells known as microglia,” said senior author Gordon Mitchell, Ph.D., deputy director of the McKnight Brain Institute.
“Recent discoveries make it clear that microglia have important functions in health,” said Mitchell, director of the University of Florida’s BREATHE Center and a professor of physical therapy. “And to our knowledge, this is the first demonstration that they play a role in regulating plasticity of any motor system or in spinal cord neurons. This is also the first demonstration that phrenic motor plasticity participates in its own regulation by interacting with other nearby cells.”
Recording activity in the phrenic nerve, which can serve as a surrogate for the brain signal to take a breath, the research team manipulated the expression of a key molecule known as fractalkine within phrenic motor neurons. During hypoxic episodes, fractalkine released from the neurons signaled to microglia to respond by producing another molecule called adenosine, which determined the extent of plasticity, the investigators reported.
Nerve activity increased briskly during each low oxygen period and, importantly, the increased activity lingered long after the hypoxic episodes ended, Mitchell said. Blocking the influence of microglia greatly increased — or decreased — this plasticity, depending on the severity of the hypoxia.
“Our next goal is to further understand how low oxygen triggers the activation of fractalkine and how to apply this knowledge in translational studies by manipulating motor-neuron microglial communication to optimize the treatment effect of therapeutic acute intermittent hypoxia,” he said.