Control of Respiratory Circuits by Brainstem Astrocytes

Background. Astrocytes, the ubiquitous electrically non-excitable glial cells of the brain, are strategically arranged in the nervous system to regulate the chemical microenvironment of neurons. Moreover, astrocytic vesicular release of gliotransmitters (e.g., ATP, D-serine) can affect the activity of neighboring neurons and neuronal circuits. Here, the brainstem respiratory network within the rat preBötzinger complex (preBötC), a functionally specialized region generating respiratory rhythm and controlling homeostatic breathing, was used as a model to assess the active role of astrocytic signaling in modulating activity of vital neural circuits. Methods. To block vesicular release mechanisms either the dominant-negative SNARE protein (dn-SNARE) or the light chain of tetanus toxin (TeLC) was selectively expressed in preBötC astrocytes by viral vector-mediated transduction. We then examined the functional perturbations of respiratory control caused by this disruption of astroglial signaling in conscious freely-moving adult rats in room air, as well as when the rats were exposed to low-O2 conditions (environmental hypoxia) or high-CO2 conditions (producing systemic hypercapnia). We also measured effects of the block of preBötC astrocytic signaling on exercise capacity – the distance that a rat can run to exhaustion. Results. Respiratory rate as well as sigh frequency were decreased in rats expressing TeLC or dn-SNARE in preBötC astrocytes. Also, astrocytic TeLC or dn-SNARE expression reduced the augmentation of respiratory activity and lung ventilation during both hypoxic and hypercapnic challenges. Moreover, exercise capacity was reduced markedly in the rats transduced to express TeLC or dn-SNARE in preBötC astrocytes when compared to the control groups.  Conclusion. These data reveal a fundamental physiological role of astroglial signaling in modulation of the key neuronal circuits controlling homeostatic breathing. Astrocytes are functionally specialized central chemosensors that rapidly detect physiological changes in the brain microenvironment and adjust the respiratory drive. Failure of this chemosensory mechanism may have adverse effects on neuronal function and may contribute to the development of neurological disease(s).