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 rhythm-generating 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.
Highlights
data illustrating the effect of dnSNARE expression in preBötC astrocytes on hypoxia-induced increases in the respiratory frequency
Group data illustrating the effect of dnSNARE
TeLC expression in preBötC astrocytes on CO2-induced increases in ƒR
Summary
All animal experiments were performed in Sprague-Dawley rats (adult males [250–270] g or neonates P2-P3 of either sex) in accordance with the European Commission Directive 2010/63/EU (European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes), the UK Home Office (Scientific Procedures) Act (1986), and the National Institutes of Health Guide for the Care and Use of Laboratory Animals, with project approval from the respective Institutional Animal Care and Use Committees. Animals were housed in a temperature-controlled facility with a normal light-dark cycle (12 h:12 h, lights on at 0700 hours). Tap water and laboratory rodent chow were provided ad libitum. To block vesicular release mechanisms in preBötC astrocytes, we developed a novel adenoviral vector (AVV) to drive the expression of dnSNARE protein[13] under the control of an enhanced GFAP promoter (Fig. 1a; Supplementary Table 1). Description of validation of the transgene efficacy in blocking vesicular release mechanisms in astrocytes is
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