Blockade of synaptic inhibition within the pre‐Bötzinger complex in the cat suppresses respiratory rhythm generation <i>in vivo</i>

Pierrefiche, Olivier; Schwarzacher, Stephan W.; Bischoff, Anne M.; Richter, Diethelm W.

doi:10.1111/j.1469-7793.1998.245bo.x

Cited by 116 publications

(113 citation statements)

References 40 publications

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“…It is therefore not surprising that greater than 50% of neurons within the pre-BötC are glycinergic, as evidenced by strong expression of GlyT2 (21,40). Furthermore, rhythmic respiratory activity is disturbed when glycinergic synapses dysfunction as a result of genetic lesions (13,41) or when GlyRs are blocked by strychnine (11,12).…”

Section: Discussionmentioning

confidence: 99%

“…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 transmission abolishes regular breathing (11)(12)(13). This has clinically significant consequences, such as prolonged breath-holding episodes (also called inspiratory apnea or apneusis; refs.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

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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“…It has been implied that the PBC functions as a central hypoxia chemosensor for respiration (44,45). The application of agonists and antagonists of some neurotransmitters and neuromodulators to the PBC can induce apparent changes in respiratory rhythm and pattern (8,21,34,41,43). However, very little is known about postnatal development of neurochemicals in the PBC when the system may be more vulnerable to respiratory distress.…”

mentioning

confidence: 99%

Postnatal expression of neurotransmitters, receptors, and cytochrome oxidase in the rat pre-Bötzinger complex

Liu

Wong‐Riley

2002

Journal of Applied Physiology

120

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Liu, Qiuli, and Margaret T. T. Wong-Riley. Postnatal expression of neurotransmitters, receptors, and cytochrome oxidase in the rat pre-Bötzinger complex. J Appl Physiol 92: 923-934, 2002; 10.1152/japplphysiol.00977.2001.-The preBötzinger complex (PBC) is postulated as the center of respiratory rhythmogenesis. Previously, we found a reduction or plateau of cytochrome oxidase (CO) activity in the PBC and other respiratory nuclei at postnatal days 3-4, despite a general increase of CO with age, suggesting a period of synaptic readjustment. The present study examined the expression of CO and a number of neurochemicals in the PBC at closer time intervals. At postnatal days 3-4 and, more prominently, at postnatal day 12, expression of CO, glutamate, and N-methyl-D-aspartate receptor subunit 1 was reduced, whereas expression of GABA, GABAB receptor, glycine receptor, and ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor subunit 2 was increased. These findings are consistent with our hypothesis that decreased CO activity is associated with an increase in inhibitory drive (mediated by GABA and glycine, their receptors, and possibly blockage of Ca 2ϩ entry by glutamate receptor subunit 2) and a decrease in excitatory drive (mediated by glutamate and its receptors). Our findings point to two critical periods during postnatal development of the rat when their respiratory system may be more vulnerable to respiratory insults.N-methyl-D-aspartate receptor subunit 1; glutamate receptor subunit 2; GABAB receptor; neurokinin-1 receptor; glutamate THE MECHANISM OF RESPIRATORY rhythmogenesis is not fully understood, but cumulative evidence suggests that the pre-Bötzinger complex (PBC) may be the center or kernel of respiratory rhythm generation (12,37,38,42). The PBC is located at the rostroventrolateral medulla, ventral to the nucleus ambiguus (NA), and can be anatomically defined by the distribution of immunoreactive neurokinin-1 receptors (NK1R) (15). Removal of only the PBC in the brain stem eliminated respiratory rhythm generation in neonatal rats (42). All six basic types of respiratory neurons were identified in the PBC (9, 42), and neurons with voltagedependent pacemaker-like properties were also found there (6,7,17,22,47). It has been implied that the PBC functions as a central hypoxia chemosensor for respiration (44,45). The application of agonists and antagonists of some neurotransmitters and neuromodulators to the PBC can induce apparent changes in respiratory rhythm and pattern (8,21,34,41,43). However, very little is known about postnatal development of neurochemicals in the PBC when the system may be more vulnerable to respiratory distress.Cytochrome oxidase (CO) is the terminal enzyme of the mitochondrial respiratory chain and is considered to be a reliable marker of neurons' metabolic capacity and levels of functional activity (51). Previously, we found that the PBC and other respiratory nuclei in the rat exhibited a general increase in CO activity with postnatal development. However, there was a distin...

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“…This suggests that the temporal relationship of activity between the different rhythm generators is relatively plastic and is capable of undergoing dynamic change. In mature cats and mice, in vivo, generation of the respiratory rhythm is dependent upon inhibitory synaptic mechanisms since pharmacological blockade of glycine and y-aminobutyric acid (GABA, subtype A) receptors suppress respiration (Paton & Richter, 1995;Pierrefiche et al 1998). In contrast, rhythmic hypoglossal discharges recorded from transverse slice preparations of mature mice persist in the presence of glycine and GABA A receptor antagonists (Ramirez et al 1996).…”

Section: Bi52ttmentioning

confidence: 99%

Cardiovascular/Respiratory Control

1998

The Journal of Physiology

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OntarioOxygen uptake (VO,) kinetics during the on-transient of moderate exercise are appreciably slower in older than in younger adults (Babcock et al. 1994), possibly because of reduced ability to deliver oxygen to the exercising muscle (Petrella et al. 1997 It is not known whether cold-induced vasodilatation (CIVD) in man (Lewis, 1930) is a local or central effect, or which part of the vascular bed is responsible (Sendowski et al. 1997). The present study was designed to provide information about this.

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Blockade of synaptic inhibition within the pre‐Bötzinger complex in the cat suppresses respiratory rhythm generation in vivo

Cited by 116 publications

References 40 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

Postnatal expression of neurotransmitters, receptors, and cytochrome oxidase in the rat pre-Bötzinger complex

Cardiovascular/Respiratory Control

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