By Miriam Frankel
A type of brain cell thought to be responsible for supporting other cells may have a previously unsuspected role in controlling breathing.
Star-shaped cells called astrocytes, found in the brain and spinal cord, can "sense" changes in the concentration of carbon dioxide in the blood and stimulate neurons to regulate respiration, according to a study published online July 15 in Science. The research may shed some light on the role of astrocytes in certain respiratory illnesses, such as cot death, which are not well understood.
Astrocytes are a type of glial cell--the most common type of brain cell, and far more abundant than neurons. "Historically, glial cells were only thought to 'glue' the brain together, providing neuronal structure and nutritional support but not more," explains physiologist Alexander Gourine of University College London, one of the authors of the study. "This old dogma is now changing dramatically; a few recent studies have shown that astrocytes can actually help neurons to process information."
"The most important aspect of this study is that it will significantly change ideas about how breathing is controlled," says David Attwell, a neuroscientist at University College London, who was not involved in the study.
During exercise, the amount of CO2 in the blood increases, making the blood more acidic. Until now, it was thought that this pH change was "sensed" by specialized neurons that signal to the lungs to expel more CO2. But the study found that astrocytes can sense such a decrease in pH too--a change that causes an increase in the concentration of calcium ions (Ca2+) in the cells and the release of the chemical messenger adenosine-5'-triphosphate (ATP). The researchers think that ATP stimulates nearby neurons that are involved with respiration; these in turn trigger increased breathing so that excess CO2 can be removed from the blood.
One of the techniques the team used was to insert a gene encoding a calcium-sensitive fluorescent protein, Case12, into the brains of living rats, along with a promoter sequence that ensured the gene would express only in astrocytes. When light was shone on the brain, Case12 fluoresced with a brightness corresponding to the concentration of calcium in the astrocytes. The team found an immediate increase in calcium when the pH level was lowered. The experiment also revealed that these astrocytes, reacting to changes in pH, are located in the medulla oblongata--an area of the brain known to "sense" the chemical composition of blood. The team observed similar results using rat brainstem slices and cell-culture models.
The researchers hope that the findings may help the understanding of respiratory-failure illnesses such as sudden infant death syndrome, also known as cot death, and a potentially fatal syndrome called Ondine's curse. If problems in glial-cell function can be shown to cause these conditions, astrocytes could perhaps be targeted in the future development of therapies.
"What this study does is beautiful and very exciting," says Philip Haydon, a neuroscientist from Tufts University School of Medicine in Boston, Mass. "The next step would be to selectively block astrocytic calcium signals or the release of ATP, then drive the pH change and see what happens--that would determine whether astrocytes are absolutely necessary in controlling breathing."
Gourine agrees that it is important to develop tools to inhibit such astrocyte responses, but says it is a "major challenge."
Brian MacVicar, a cellular neuroscientist from the University of British Columbia in Vancouver, Canada, says that there has been some disagreement about the interaction between astrocytes and neurons. The question is whether astrocytes can really do anything rapidly enough to alter ongoing behavior by influencing neuron activity, he says, or if they have a more passive role.
"The astrocytes are shown here to respond rapidly -- within seconds -- to a physiological stimulus," he says. "The impact of this paper will convince the most hardened skeptic that astrocytes can change neuronal activity in response to a stimulus and thereby alter a behavioral response."
But some researchers say that caution is needed in interpreting data from such animal studies. "Everybody can probably agree that astrocytes can signal to neurons in cell culture," says Attwell. "But the problem is that when you want to move that into living organisms, it is more complicated to interpret the data, and especially to determine exactly what the signaling mechanism is."