Astrocytes modulate brainstem respiratory rhythm-generating circuits and determine exercise capacity

Abstract

Astrocytes are implicated in modulation of neuronal excitability and synaptic function, but it remains unknown if these glial cells can directly control activities of motor circuits to influence complex behaviors in vivo. This study focused on the vital respiratory rhythmgenerating circuits of the preBötzinger complex (preBötC) and determined how compromised function of local astrocytes affects breathing in conscious experimental animals (rats). Vesicular release mechanisms in astrocytes were disrupted by virally driven expression of either the dominant-negative SNARE protein or light chain of tetanus toxin. We show that blockade of vesicular release in preBötC astrocytes reduces the resting breathing rate and frequency of periodic sighs, decreases rhythm variability, impairs respiratory responses to hypoxia and hypercapnia, and dramatically reduces the exercise capacity. These findings indicate that astrocytes modulate the activity of CNS circuits generating the respiratory rhythm, critically contribute to adaptive respiratory responses in conditions of increased metabolic demand and determine the exercise capacity.

CrossTalk proposal: a central hypoxia sensor contributes to the excitatory hypoxic ventilatory response

“…; Sheikhbahaei et al . ). Second, viral approaches that expressed the light chain of tetanus toxin (TeLC) or dnSNARE to disrupt vesicular release mechanisms selectively in preBötC astrocytes reduced the HVR in (i) anaesthetized rats; (ii) awake CB‐denervated rats; and (iii) most importantly, awake rats with intact peripheral chemoreceptors, as this addressed the potentially confounding effects of anaesthesia and removal of "permissive" CB input (Fig B; Angelova et al .…”

“…; Sheikhbahaei et al . ). It will be important to demonstrate that the reduced HVR following TeLC or dnSNARE expression in preBötC astrocytes is not due to non‐specific disruption of glial function and impaired ability of the preBötC to increase ventilation.…”

Rebuttal from Gregory D. Funk and Alexander V. Gourine

“…; Sheikhbahaei et al . ). Three types of preBötC astrocytes have been distinguished based solely on electrophysiological properties (Grass et al .…”

“…; Sheikhbahaei et al . ). This is seen also in anaesthetized CB intact or peripherally chemodenervated animals (Gourine et al .…”

“…; Sheikhbahaei et al . ) strongly challenge the prevailing dogma that the entire hypoxia‐induced increase in ventilation originates from the carotid body (CB; or other peripheral chemoreceptor site).…”