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Serotonergic neurons as carbon dioxide sensors that maintain ph homeostasis

Nature Reviews Neuroscience volume 5, pages 449–461 (2004)Cite this article

Key Points

  • One of the essential tasks for maintaining life is breathing, which not only ensures a normal supply of oxygen to tissues, but also maintains carbon dioxide levels within a narrow range. Central chemoreceptors in the brainstem monitor carbon dioxide levels and control lung ventilation. Recent data indicate that serotonergic neurons are chemoreceptors.

  • There is a high concentration of serotonin (5-hydroxytryptamine or 5-HT)-immunoreactive nerve terminals within the main respiratory nuclei, and these nuclei also contain nerve terminals that are immunoreactive for substance P and thyrotropin-releasing hormone (TRH). The nerve terminals arise from serotonergic neurons in the medullary raphé and ventrolateral medulla.

  • Serotonergic neurons seem primarily to have an excitatory effect on breathing, and they are thought to provide tonic drive to maintain respiratory output during wakefulness. However, there is evidence that 5-HT can have an inhibitory effect on some elements of the network that controls respiratory output, and a subset of 5-HT neurons might inhibit respiratory output.

  • Changes in arterial carbon dioxide probably influence breathing indirectly through changes in brain pH. Medullary serotonergic neurons are highly sensitive to pH, and their relationship with blood vessels is consistent with a specialized role as arterial carbon dioxide sensors. Lesions of these neurons lead to blunting of the ventilatory response to increased carbon dioxide.

  • 5-HT, TRH and substance P enhance excitability of the respiratory network through numerous mechanisms and at multiple sites within the respiratory network, including rhythm-generating neurons, respiratory premotor neurons and respiratory motor neurons.

  • Serotonergic neurons in the midbrain also sense carbon dioxide, and these neurons might have a role in inducing various non-respiratory effects in response to a rise in carbon dioxide, such as arousal from sleep, anxiety and changes in cerebrovascular tone.

  • A role for serotonergic neurons in pH control might help to explain how three seemingly unrelated human disorders — sudden infant death syndrome (SIDS), panic disorder and migraine — could all be linked to this single, relatively homogeneous, small group of neurons. Some cases of SIDS have been attributed to defects in the 5-HT system.

Abstract

Serotonergic neurons in the medulla have recently been shown to be sensors of carbon dioxide and pH. There is compelling evidence that the co-release of serotonin, substance P and thyrotropin-releasing hormone from these neurons stimulates the neural network that controls breathing at numerous sites using many different mechanisms. Serotonergic neurons in the midbrain are also chemosensitive, and might mediate non-respiratory responses to increased carbon dioxide, such as arousal. This role in control of pH homeostasis could provide a neurobiological explanation for the link between changes in the serotonin system and sudden infant death syndrome (SIDS).

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Figure 1: Respiratory control and serotonin.
Figure 2: Medullary serotonergic neurons are carbon dioxide/pH sensors.
Figure 3: In vivo evidence for central chemoreception in the medullary raphé.
Figure 4: Mechanisms of respiratory stimulation by raphé neurotransmitters.
Figure 5: Midbrain raphé neurons are also carbon dioxide/pH sensors.
Figure 6: The blind men and the elephant.

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Acknowledgements

This author is supported by grants from the National Heart, Lung and Blood Institute, the National Institute for Child Health and Human Development and the Veterans Administration Medical Center.

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  1. Departments of Neurology, and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA

    George B. Richerson

  2. Veteran's Affairs Medical Center, West Haven, Connecticut, USA

    George B. Richerson

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DATABASES

Entrez Gene

5-HT1a

5-HT1b

5-HT2a

5-HT4a

NK1

PET1

substance P

TASK1

TRH

OMIM

SIDS

FURTHER INFORMATION

Richerson's homepage

Glossary

RAPHé NUCLEI

A series of neuronal groups located along the midline of the brainstem. They constitute the main supply of 5-hydroxytryptamine (5-HT) to the rest of the brain.

SUBSTANCE P

Substance P is an 11-amino-acid tachykinin peptide neurotransmitter that binds preferentially to the neurokinin (NK)1 receptor. A second tachykinin, NKA, also has high affinity for this receptor, suggesting that to refer to the NK1 receptor as 'the substance P receptor' could be misleading.

NEONATAL RAT IN VITRO BRAINSTEM SPINAL CORD

The medulla and spinal cord are removed en bloc and placed dorsal side down in a dish. This preparation has been very important for in vitro studies of the intact respiratory network.

TONIC

Physiological events that occur in a sustained manner, unlike phasic events, which occur only transiently with intervening periods of inactivity.

RESPIRATORY NEURONS

Neurons that fire in phase with output to respiratory muscles. They can be divided into inspiratory neurons and expiratory neurons on the basis of when the peak of activity occurs.

IONTOPHORESIS

The introduction of a substance by ion transfer by applying an electrical potential across an electrode.

AFTERHYPERPOLARIZATION

The membrane hyperpolarization that follows the occurrence of an action potential.

BASILAR ARTERY

The main blood supply to the brainstem, it is formed by the confluence of the vertebral arteries – which are two of the four arteries that supply the brain.

C-FOS

An immediate early gene that is activated by neuronal firing. it is often used to identify neurons responsive to a particular stimulus in vivo.

S-TYPE POTASSIUM CHANNEL

A barium-insensitive outwardly rectifying potassium channel.

HYPOGLOSSAL NERVE

Innervates the genioglossus muscle in the tongue. This is an accessory respiratory muscle that helps maintain airway patency during inspiration.

LONG-TERM POTENTIATION

(LTP). An enduring increase in the amplitude of excitatory postsynaptic potentials as a result of high-frequency (tetanic) stimulation of afferent pathways. It is measured both as the amplitude of excitatory postsynaptic potentials and as the magnitude of the postsynaptic-cell population spike. LTP is most often studied in the hippocampus and is often considered to be the cellular basis of learning and memory in vertebrates.

GOLGI STAINING

A histological staining technique that involves impregnating the tissue with silver nitrate. This labels a random subset of neurons, allowing the entire cell and its processes to be visualized.

DYSPNEA

The uncomfortable awareness of breathing or being 'short of breath'.

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Richerson, G. Serotonergic neurons as carbon dioxide sensors that maintain ph homeostasis. Nat Rev Neurosci 5, 449–461 (2004). https://doi.org/10.1038/nrn1409

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