Serotonin receptors: guardians of stable breathing

Richter, Diethelm W.; Manzke, Till; Wilken, Bernd; Ponimaskin, Evgeni

doi:10.1016/j.molmed.2003.10.010

Cited by 166 publications

(139 citation statements)

References 65 publications

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“…The activation of 5-HTR 1A potentiated glycinergic currents in all postsynaptic neurons receiving glycinergic inputs, including inhibitory glycinergic neurons themselves (Figure 2). The 5-HTR 1A -induced potentiation of postsynaptic GlyRα3 inhibition of glycinergic neurons will depress their output discharges and cause disinhibition in the postsynaptic neurons they innervate (10,15). This is consistent with a previous report (21) demonstrating that systemic 5-HTR 1A stimulation induces powerful depression of the discharge of inhibitory early-inspiratory neurons.…”

Section: Discussionsupporting

confidence: 89%

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Serotonin receptor 1A–modulated phosphorylation of glycine receptor α3 controls breathing in mice

Manzke¹,

Niebert²,

Koch³

et al. 2010

J. Clin. Invest.

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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-HTR 1A -specific) modulation directly induced dephosphorylation of GlyRα3 receptors, which augmented inhibitory glycine-activated chloride currents in HEK293 cells coexpressing 5-HTR 1A and GlyRα3. The 5-HTR 1A -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-HTR 1A activation failed to remedy opioid-induced respiratory depression in these mice. Delineation of this 5-HTR 1A -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.

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Section: Discussionsupporting

confidence: 89%

“…13). Similar breathing difficulties can also occur following ischemia and stroke (18,19) and as a result of deep anesthesia (20), opiate abuse (21), head trauma, degenerative brain diseases (15), and alcoholism (22).…”

Section: Introductionmentioning

confidence: 99%

Serotonin receptor 1A–modulated phosphorylation of glycine receptor α3 controls breathing in mice

Manzke¹,

Niebert²,

Koch³

et al. 2010

J. Clin. Invest.

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“…We then analyzed two Phox2b-negative cell groups that are essential for normal breathing: the pre-Bötzinger complex (preBötC), a region critical for respiratory rhythm generation (22,23), and the medullary 5HT neurons, which have been proposed as a principal site of CO 2 chemoreception (2) and are important modulators of respiration (24). In neonatal rodents, the preBötC has been anatomically defined by its location ventral to the nucleus ambiguus (nA) and its expression of NK1R (25,26).…”

Section: Resultsmentioning

confidence: 99%

A human mutation in Phox2b causes lack of CO ₂ chemosensitivity, fatal central apnea, and specific loss of parafacial neurons

Dubreuil

Ramanantsoa

Trochet

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

279

331

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Breathing is maintained and controlled by a network of neurons in the brainstem that generate respiratory rhythm and provide regulatory input. Central chemoreception, the mechanism for CO2 detection that provides an essential stimulatory input, is thought to involve neurons located near the medullary surface, whose nature is controversial. Good candidates are serotonergic medullary neurons and glutamatergic neurons in the parafacial region. Here, we show that mice bearing a mutation in Phox2b that causes congenital central hypoventilation syndrome in humans breathe irregularly, do not respond to an increase in CO2, and die soon after birth from central apnea. They specifically lack Phox2b-expressing glutamatergic neurons located in the parafacial region, whereas other sites known or supposed to be involved in the control of breathing are anatomically normal. These data provide genetic evidence for the essential role of a specific population of medullary interneurons in driving proper breathing at birth and will be instrumental in understanding the etiopathology of congenital central hypoventilation syndrome.brainstem ͉ congenital central hypoventilation syndrome ͉ neurodegenerative disease ͉ respiration

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“…Because serotonergic neurons collectively innervate all the brain regions that are essential to breathing (Lindsay and Feldman, 1993;Bonham, 1995;Schwarzacher et al, 2002;Manzke et al, 2003;Richter et al, 2003), many other mechanisms in addition to their putative intrinsic response to acidification could account for the role of these neurons in the chemoreflex.…”

Section: Introductionmentioning

confidence: 99%

Serotonergic Neurons Activate Chemosensitive Retrotrapezoid Nucleus Neurons by a pH-Independent Mechanism

Mulkey¹,

Rosin²,

West³

et al. 2007

J. Neurosci.

141

188

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Serotonin activates respiration and enhances the stimulatory effect of CO 2 on breathing. The present study tests whether the mechanism involves the retrotrapezoid nucleus (RTN), a group of medullary glutamatergic neurons activated by extracellular brain pH and presumed to regulate breathing. We show that the RTN is innervated by both medullary and pontine raphe and receives inputs from thyrotropin-releasing hormone (TRH) and substance P-expressing neurons. Coexistence of serotonin and substance P in terminals within RTN confirmed that lower medullary serotonergic neurons innervate RTN. In vivo, unilateral injection of serotonin into RTN stimulated inspiratory motor activity, and pH-sensitive RTN neurons were activated by iontophoretic application of serotonin or substance P. In brain slices, pH-sensitive RTN neurons were activated by serotonin, substance P, and TRH. The effect of serotonin in slices was ketanserin sensitive and persisted in the presence of glutamate, GABA, glycine, and purinergic ionotropic receptor antagonists. Serotonin and pH had approximately additive effects on the discharge rate of RTN neurons, both in slices and in vivo. In slices, serotonin produced an inward current with little effect on conductance and had no effect on the pH-induced current. We conclude that (1) RTN receives input from multiple raphe nuclei, (2) serotonin, substance P, and TRH activate RTN chemoreceptors, and (3) excitatory effects of serotonin and pH are mediated by distinct ionic conductances. Thus, RTN neurons presumably contribute to the respiratory stimulation caused by serotonergic neurons, but serotonin seems without effect on the cellular mechanism by which RTN neurons detect pH.

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Serotonin receptors: guardians of stable breathing

Cited by 166 publications

References 65 publications

Serotonin receptor 1A–modulated phosphorylation of glycine receptor α3 controls breathing in mice

Serotonin receptor 1A–modulated phosphorylation of glycine receptor α3 controls breathing in mice

A human mutation in Phox2b causes lack of CO ₂ chemosensitivity, fatal central apnea, and specific loss of parafacial neurons

Serotonergic Neurons Activate Chemosensitive Retrotrapezoid Nucleus Neurons by a pH-Independent Mechanism

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Serotonin receptors: guardians of stable breathing

Cited by 166 publications

References 65 publications

Serotonin receptor 1A–modulated phosphorylation of glycine receptor α3 controls breathing in mice

Serotonin receptor 1A–modulated phosphorylation of glycine receptor α3 controls breathing in mice

A human mutation in Phox2b causes lack of CO 2 chemosensitivity, fatal central apnea, and specific loss of parafacial neurons

Serotonergic Neurons Activate Chemosensitive Retrotrapezoid Nucleus Neurons by a pH-Independent Mechanism

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A human mutation in Phox2b causes lack of CO ₂ chemosensitivity, fatal central apnea, and specific loss of parafacial neurons