Astrocytes release prostaglandin E2 to modify respiratory network activity

David Forsberg, Thomas Ringstedt, Eric Herlenius
  • eLife, October 2017, eLife
  • DOI: 10.7554/elife.29566

Astrocytic stars participate in and modify brainstem networks that generate breathing

What is it about?

Star-shaped cells called astrocytes are much more than simple support cells in the brain. In a new study on mice, researchers at Karolinska Institutet demonstrate that they also play a key part in the respiratory centre of the brainstem and release inflammatory molecules that regulate breathing. The results, which are presented in the scientific journal eLife, can provide important clues as to the causes of respiratory disease and the sudden unexpected postnatal collapse of newborn infants (SUPC). The control of breathing is essential for life. Without an adequate response to increased carbon dioxide levels, people can suffer from breathing disturbances, sickness, and panic. In a worst-case scenario, it can lead to premature death, as in sudden infant death syndrome. While it is known that respiration is regulated by the brainstem, just how this occurs remains very much a mystery. We know there are control mechanisms that cause the body to react to changing blood concentrations in CO2, thereby preventing death. Eric Herlenius’s research group at Karolinska Institutet has previously shown that the molecule prostaglandin E2 (PGE2), which is normally released during inflammation and fever, is triggered in the brainstem at high levels of CO2, influencing the pattern and characteristics of respiration. The group has now shown that so-called non-neuronal astrocytes in the respiratory centre of the brainstem secrete this molecule. “Astrocytes were once viewed just as a kind of glue that holds everything in place in the brain. Then they were considered as mere housekeepers providing structural and metabolic support for neurons. However, new research shows that they are involved in several vital processes, including respiration,” says Eric Herlenius, professor of paediatrics at the Department of Women’s and Children’s Health. “Our study shows that the astrocytes play an important part in the regulation of breathing by affecting the neurons and their network activity.” To study the role of astrocytes in respiration, the researchers used an in-house developed technique in which part of the brainstem of a mouse is kept alive in a special culture dish. For several weeks nerve cells and astrocytes continue to be interconnected, and can transmit signals and generate rhythmic motor neuron activity as if they were “breathing”. The mice astrocytes were labelled with a fluorescent molecule, and contained a receptor that the researchers could stimulate in order to activate them. While most of the astrocytes seemed not to participate in rhythm generation, some of them formed their own functional network in the respiratory centre, displaying rhythmic activity similar to the nerve cells. These astrocytes integrated with the nerve cells, influencing their activity and consequently respiration. “We knew that the astrocytes have the capacity of signalling just before inspiration but not that there’s this kind of connection from the astrocytes to the neurons,” says the study’s lead author David Forsberg, doctoral student at the same department. “Our hypothesis is that the astrocytes adjust the respiratory process with the help of the inflammatory molecule PGE2, and in doing so links breathing with the inflammatory system.” Interestingly, the role of astrocytes seemed to differ between the two brainstem respiratory centres that were studied. In one, astrocyte activation caused an increase in nerve cell activity, whilst in the other, nerve cell activity remained unaffected. This suggests the presence of different types of astrocytes, and a diverse distribution of them in the brainstem. Activation of the astrocytes also caused raised levels of PGE2 and weakened the respiratory centre’s reaction to high CO2 concentrations, suggesting that the astrocytes become fatigued. Since PGE2 is released during inflammation and fever, the researchers suggest that these conditions disrupt normal physiological reactions to CO2, which can lead to potentially life-threatening breathing problems. “We now want to find out if astrocyte fatigue can explain phenomena like SUPC, when newborn babies suddenly develop respiratory problems,” says Dr Forsberg. “Birth triggers a powerful stress reaction in the baby, which gives rise to high PGE2 levels. This has beneficial effects on newborn but we think this can be dangerous in combination with high levels of CO2.”

Why is it important?

The development and plasticity of brainstem neural networks and their response to environmental stresses such as hypoxia and hypercarbia are essential for life. An improved knowledge of the neural components, their interactions and development in the brainstem respiratory circuits is crucial for our comprehension of breathing and its control in children and adults. Brainstem respiration related CO2/pH-sensitive cells are involved in sleep apnea disorders, and their early development is vital for future health and their potential dysfunction can have dire acute and long-term consequences for health. The conceptual change introduced by our data that endogenous prostaglandins are central pathogenic factors in cardiorespiratory disorders, the hypoxic as well as the hypercarbic response, open new diagnostic and therapeutic avenues that should significantly better the diagnostics and treatment of newborns infants and children with apneas and respiratory dysfunction.

Perspectives

MD, PhD Eric Herlenius (Author)
Karolinska Institutet

No effective pharmacological treatment of central breathing dysfunction, besides caffeine with potential side effects, exists at present. The use of anti-inflammatory drugs in the treatment of apnea of prematurity and apnea syndromes could be a possible breakthrough and extend our armamentarium in the management of breathing disorders. Paracetamol is a well-established drug, with known therapeutic doses, that affects the prostaglandin pathway and may help in stabilizing neonatal respiration.

The following have contributed to this page: MD, PhD Eric Herlenius