Abstract
Rhythmic breathing movements originate from a dispersed neuronal network in the medulla and pons. Here, we demonstrate that rhythmic activity of this respiratory network is affected by the phosphorylation status of the inhibitory glycine receptor α3 subtype (GlyRα3), which controls glutamatergic and glycinergic neuronal discharges, subject to serotonergic modulation. Serotonin receptor type 1A-specific (5-HTR1A-specific) modulation directly induced dephosphorylation of GlyRα3 receptors, which augmented inhibitory glycine-activated chloride currents in HEK293 cells coexpressing 5-HTR1A and GlyRα3. The 5-HTR1A-GlyRα3 signaling pathway was distinct from opioid receptor signaling and efficiently counteracted opioid-induced depression of breathing and consequential apnea in mice. Paradoxically, this rescue of breathing originated from enhanced glycinergic synaptic inhibition of glutamatergic and glycinergic neurons and caused disinhibition of their target neurons. Together, these effects changed respiratory phase alternations and ensured rhythmic breathing in vivo. GlyRα3-deficient mice had an irregular respiratory rhythm under baseline conditions, and systemic 5-HTR1A activation failed to remedy opioid-induced respiratory depression in these mice. Delineation of this 5-HTR1A-GlyRα3 signaling pathway offers a mechanistic basis for pharmacological treatment of opioid-induced apnea and other breathing disturbances caused by disorders of inhibitory synaptic transmission, such as hyperekplexia, hypoxia/ischemia, and brainstem infarction.
Highlights
The motor control of regular rhythmic breathing of mammals originates from a neuronal network in the lower brainstem that includes the bilateral ventral groups of respiratory neurons (VRG) with the pre–Bötzinger complex and receives important feedback control through postinspiratory neurons of the pontine respiratory group (PRG; refs. 3, 4)
glycine transporter 2 (GlyT2)-negative cells, but unexpectedly, in the BötC and pre-BötC, which is essential for respiratory rhythm generation [1, 2], glycine receptor α3 subtype (GlyRα3) was expressed in GlyT2-positive cells (Figure 1, B and C)
In vivo, respiratory activity is generated by the pre-BötC, which communicates with the adjacent VRG and with respiratory neurons in the pons [1, 3, 4]
Summary
The motor control of regular rhythmic breathing of mammals originates from a neuronal network in the lower brainstem that includes the bilateral ventral groups of respiratory neurons (VRG) with the pre–Bötzinger complex (pre-BötC; refs. 1, 2) and receives important feedback control through postinspiratory neurons of the pontine respiratory group (PRG; refs. 3, 4). Inhibitory synaptic interactions are vital, as they both impose the voltage changes required for initiation of endogenous respiratory bursting and control the burst pattern Another indispensable function of these interactions is to terminate respiratory bursts during transitions among the distinct phases of the respiratory cycle that are determined by activity of antagonistic neurons [8,9,10]. This critical process of burst termination is largely controlled by glycine receptors (GlyRs), since dysfunction or deletion of inhibitory glycinergic
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