Astrocytic Connexin43 Channels Are Essential for Breathing Pattern Stabilization in the preBötzinger Complex

Area of Science:

• Neuroscience
• Respiratory Physiology
• Astrocyte Biology

Background:

• Astrocytes in the preBötzinger complex (preBötC) play a key role in respiratory rhythm and pattern generation.
• The precise molecular mechanisms by which astrocytes influence breathing remain largely unknown.
• Connexin 43 (Cx43) is a major connexin protein expressed in preBötC astrocytes.

Purpose of the Study:

• To investigate the essential role of connexin 43 (Cx43) channels in preBötC astrocytes for stabilizing breathing patterns.
• To elucidate the molecular mechanisms underlying astrocyte contributions to respiratory regulation.

Main Methods:

• Utilized whole-body plethysmography, in vivo fiber photometry, and phrenic nerve discharge (PND) recordings.
• Employed photostimulation, RNAscope in situ hybridization, and RNA sequencing.
• Investigated the effects of Cx43 channel modulation and astrocytic Gja1 knockdown in mice.

Main Results:

• PreBötC astrocyte activation correlated with specific respiratory events like sighs.
• Cx43 (Gja1) was the predominant connexin transcript in preBötC astrocytes.
• Modulating Cx43 hemichannels affected breathing frequency, PND, and activated preBötC^SST neurons via ATP release and P2Y1 receptors.

Conclusions:

• Identified an astrocyte-to-neuron signaling pathway involving Cx43 hemichannels, ATP release, and P2Y1 receptors on preBötC^SST neurons.
• Cx43 hemichannels are critical molecular components for stabilizing respiratory patterns.
• This study provides new insights into astrocyte-neuron communication in respiratory control.