Inhibitory Signals in Brain May Underlie Breathing Problems in Rett
Abnormally slow or shallow breathing in Rett syndrome develops in part due to altered inhibitory signals in the brain, research done in a rat model of the disease suggests.
Data also indicate that therapeutic approaches that amplify the brain’s inhibitory signals might be useful for Rett-related breathing problems.
These findings were in the study “In vivo evidence for the cellular basis of central hypoventilation of Rett syndrome and pharmacological correction in the rat model,” published in the Journal of Cellular Physiology.
Hypoventilation — abnormally slow or shallow breathing that makes it hard for the body to get enough oxygen — can be a common Rett symptom. The biological processes that cause such hypoventilation are not very well understood; unraveling these processes may open the door to future treatments.
Scientists at Georgia State University in Atlanta conducted a series of studies in male rats with mutations in the rat form of the MECP gene — the most common cause of Rett syndrome — to better understand these processes. Specifically, the researchers analyzed the behavior of neurons (nerve cells) in the rats’ brainstem — the lowest part of the brain — which controls breathing.
Intuitively, the team had expected that slow or shallow breathing might be associated with lower neuronal activity. However, they found the exact opposite: Rett model rats appeared to have abnormally high levels of electrical activity in the neurons that control breathing.
As an example, the phrenic nerve — a nerve that runs from the neck to the diaphragm, and is crucial in controlling breath — is usually only activated when mammals inhale. However, in these rats, the researchers also noted expiratory phrenic activity. In other words, the phrenic nerve was firing when it normally would, when the rats inhaled, and when it normally wouldn’t, when they exhaled.
The scientists postulated that this increased activity may lead to hypoventilation because it throws the brain out of sync. Normally, the neural activity that governs breathing has to occur in specific rhythms: first, the neurons that signal to inhale activate, and then the neurons that signal to exhale activate. Abnormally high activity could disrupt this rhythm, ultimately impairing breathing.
The researchers then explored the molecular basis for this excessive activity. Neurons communicate with each other by sending chemical messengers called neurotransmitters, which regulate the neurons’ electrical activity. At a simple level, there are two kinds of neurotransmitters: excitatory ones, which prompt a nerve cell to fire; and inhibitory ones, which decrease the likelihood of neurons firing.
One of the main inhibitory neurotransmitters used in the brain is called GABA, and deficient GABAergic inhibition has been reported in the brain of Rett patients.
Since Rett rats had unusual neuronal activity, the researchers reasoned that they might be lacking inhibitory signals that would otherwise suppress such activity. To test this, the team treated rats with NNC‐711 or THIP, two chemicals that basically work by increasing GABA activity.
Treatment with these compounds had robust effects in correcting abnormal phrenic activity, and in easing hypoventilation in the rats.
Notably, these GABA-targeting treatments were highly beneficial for rats with such severe breathing difficulties that would have been euthanized for humane reasons. In three out of five rats, the treatment “extended their lifespan by ~20 days with no obvious [breathing problems] during the period,” the researchers reported.
“The GABAergic [GABA-enhancing] intervention in this study not only provides evidence for dedicated cellular mechanisms but also suggests potential pharmacological intervention,” the team wrote.