Astrocytic contribution to glutamate-related central respiratory chemoreception in vertebrates
Introduction
The respiratory pattern generator (RPG) is the neural network in charge of originating and shaping the respiratory rhythm in mammals (Del Negro et al., 2018; Feldman et al., 2013; Ramirez and Baertsch, 2018b; Von Euler, 1986). This neural network starts its activity early in fetal life and continues, relentlessly, sustaining breathing from birth up to death (Champagnat and Fortin, 1997; Champagnat et al., 2011; Fortin et al., 1995; Thoby-Brisson et al., 2005). RPG neurons are located at the brainstem along the ventral (VRC) and the dorsal (DRC) respiratory columns (Feldman et al., 2013; Von Euler, 1986). RPG neurons project into cranial (V, VII, IX, X, XII) and spinal cord (C3-C6, T1-T10) nuclei (Del Negro et al., 2018; Feldman et al., 2013; Fogarty et al., 2018; Von Euler, 1986), to innervate motoneurons that synapse with respiratory muscles to control the resistance of the airway pathway, the rigidity and expansion of the thoracic wall, and the generation of the air pressure gradient to insuflate the lungs (Von Euler, 1986). The RPG contains three main microcircuits in the VRC (Ramirez and Baertsch, 2018a). A first one is found at the rostral medulla, around the facial nucleus, the retrotrapezoid/parafacial respiratory group (RTN/pFRG), in charge of pre-inspiration, originated from phox2b expressing progenitors (Feldman et al., 2013; Onimaru and Homma, 2003); a second one, the preBötzinger Complex (preBötC), is in charge of inspiration, which is derived from Dbx1 progenitors (Feldman et al., 2013; Smith et al., 1991). Although controversial (Toor et al., 2019), the post inspiratory activity found in phrenic neurogram has been proposed to be originated from a third microcircuit, the post inspiratory complex (PiCo) (Anderson et al., 2016). This complex is located caudal to the facial nucleus in an area dorsal and medial to the ambiguous nucleus and it is constituted by glutamatergic-cholinergic neurons (Anderson et al., 2016). Interestingly, it has been proposed that the ensemble of these three microcircuits originates the three phases of the mammalian respiratory rhythm (Anderson and Ramirez, 2017; Ramirez and Baertsch, 2018a; Richter et al., 1992). (Anderson et al., 2016; Anderson and Ramirez, 2017; Feldman et al., 2013; Onimaru and Homma, 2003; Ramirez and Baertsch, 2018a; Richter et al., 1992; Smith et al., 1991). Chemoreception is one of the main sensory modalities controlling the mammalian RPG activity. Peripheral arterial chemoreceptors (carotid and aortic bodies) inform to the RPG about changes in PaO2, PaCO2, pH, blood flow, osmolarity, and temperature occurring at the level of great arteries (Eyzaguirre et al., 1983; Iturriaga et al., 2021). In addition, central chemoreceptors provide information about changes in pH or PaCO2 in the interstitial and the cerebrospinal fluid at different regions of the brain, in particular from several brainstem nuclei (Coates et al., 1993; Feldman et al., 2003; Guyenet, 2014; Nattie, 1998; Nattie and Li, 2012).In this review we will describe the main characteristics of central chemoreception in mammals. We analyze evidence of central chemoreception in other vertebrates, in an attempt to elucidate when some features of the astrocytic contribution to central chemoreception and its glutamate-dependent mechanisms emerge in the vertebrate lineage. Table 1 summarizes drugs or modulators mentioned in the text and their effects on the respiratory frequency.
Section snippets
Central chemoreception in mammals
The mammalian central chemoreception and its contribution to breathe regulation has been extensively studied (Coates et al., 1993; Eugenin Leon et al., 2016; Feldman et al., 2003; Guyenet, 2014; Nattie, 1998; Nattie and Li, 2012; Richerson, 2004). Central chemoreceptors, that is, cells able to sense and be activated by increased H+ concentrations (acidosis) or increased levels of CO2 (hypercapnia) (Coates et al., 1993; Eugenin Leon et al., 2016; Feldman et al., 2003; Guyenet, 2014; Nattie, 1998
Glutamate and central chemoreception
Glutamate is the principal excitatory neurotransmitter of the central nervous system, playing with its receptors, a key role in the regulation of excitatory/inhibitory balance of neuronal circuits (Burrell and Sahley, 2001). Glutamate receptors have been classified according to their associated transduction mechanisms and are divided into metabotropic (associated with G protein) and ionotropic (associated with permeable ion channel) (Hollmann and Heinemann, 1994). Ionotropic receptors,
Phylogenetic analysis of the ionotropic glutamate receptors
Phylogenetic analyzes have shown that ionotropic glutamate receptors (iGluR) in mammals evolved from simpler signaling mechanisms (Stroebel and Paoletti, 2020). A form of iGluR has been seen in a plant variety, which suggests that eukaryotes have used glutamate or some other amino acid as a signaling molecule before they evolved nervous systems (Lam et al., 1998; Turano et al., 2001), but they do not exhibit the properties of NMDA receptors (NMDAR) (Stroebel and Paoletti, 2020). On the other
Glutamate involvement in generation and modulation of the respiratory rhythm
In this section we show that the pharmacological manipulation of the glutamatergic transmission in the respiratory neural network have revealed some functional peculiarities when results are compared among different mammalian species. In anaesthetized cats, the injection of glutamate agonists into the rostral ventrolateral medulla (RVLM) increases ventilation (Li and Nattie, 1995; Nattie and Li, 1995), whereas the microinjection of glutamate antagonists, like kynurenic acid, a non-selective
Glutamate contribution to the central respiratory chemoreception
Most data obtained by ionotropic or metabotropic glutamate receptor blockade within specific brainstem nuclei or areas suggest that the blockade of ionotropic glutamate receptors reduces the hypercapnia-induced hyperventilation (Moreira et al., 2006; Nattie et al., 1993; Takakura and Moreira, 2011; Taxini et al., 2013). However, there are exceptions, like the rostral raphe medullary area in rats and the nucleus isthmi in amphibians, in which blockade of ionotropic glutamate receptors exerts an
CO2/H+ -sensitivity in neurons
Neurons able to sense CO2/H+ has been found in the hypothalamus (Williams et al., 2007), the NTS (Dean et al., 1990), the RVLM (Kawai et al., 2006; Richerson, 1995), the preBötC (Solomon et al., 2000), the pFRG/RTN(Mulkey et al., 2004; Onimaru et al., 2008, 2012), the RN (Richerson, 2004; Wang et al., 1998; Wang and Richerson, 1999), and the LC (Cui et al., 2011; Li and Putnam, 2013). Intrinsic chemosensitivity has been demonstrated in acutely dissociated cell cultures only in RN and RTN
Phylogenetic aspects of astrocytes
The nervous system is an exclusive characteristic of Animalia Kingdom (Verkhratsky et al., 2019). Although several issues about the origin and evolution of the nervous system are still under debate (Strausfeld and Hirth, 2015), the most primitive version of nervous system, the “diffuse”, non-centralized, nervous system appears already in Ctenophora (comb jellies) and Cnidarians (hydras and sea jellies) (Verkhratsky et al., 2019).
This primitive diffuse nervous system is formed only by
Lamprey
Like other neural CNS circuits involved in motor activities (Grillner, 2006; Grillner et al., 2013), the respiratory neural network has several characteristics highly conserved along vertebrate evolution (Cinelli et al., 2013; Milsom, 2010; Wilson et al., 2006). In fact, even the lamprey, the oldest extant vertebrate that diverged from the main vertebrate line more than 500 million years ago (Kumar and Hedges, 1998), has a central pattern generator (CPG), the paratrigeminal respiratory group
Concluding remarks
Mammalian central chemoreception and the contribution of astrocytes have received considerable attention in the last years resulting in a great number of reports characterizing and unraveling the underlying mechanisms. By contrast, less attention has been focused on studying central chemoreception in the other members of the subphyla vertebrata of chordates (fish, amphibians, reptiles, and birds). This means, that a complete information about the structure, location, and modulators of central
Author contributions
MJO performed partial bibliographic search, partial writing of review and design of figures; AF performed partial bibliographic search, partial writing of review and design of figures; RvB participated in the funding of the work and writing of all versions of the manuscript; and JE participated in the design, supervision, funding of the work, and the writing of all versions of the manuscript.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgements
The current study was supported by grants Fondo Nacional del Desarrollo de la Ciencia y Tecnología (FONDECYT)1211359 (JE) and 1171645 (RvB); Conicyt Redes190187 (RvB). Comisión Nacional de Ciencia y Tecnología (CONICYT)#21211042 (AF); MJO was a fellow postdoc (Proyecto 021843 EL_POSTDOC, Resolución 368 USACH). AF is student of the PhD Program in Neuroscience, Universidad de Santiago de Chile.
References (269)
- et al.
Purinergic signalling in the nervous system: an overview
Trends Neurosci.
(2009) - et al.
Gliotransmitters travel in time and space
Neuron
(2014) - et al.
Molecular cloning, genomic organization, and functional expression of Na+/H+ exchanger isoform 5 (NHE5) from human brain
J. Biol. Chem.
(1999) - et al.
The NMDA receptor’ glycine modulatory site’ in schizophrenia: D-serine, glycine, and beyond
Curr. Opin. Pharmacol.
(2015) - et al.
Glia: the many ways to modulate synaptic plasticity
Neurochem. Int.
(2010) - et al.
A neuron-glia signalling network in the active brain
Curr. Opin. Neurobiol.
(2001) - et al.
Role of glutamate receptor subtypes in the lamprey respiratory network
Brain Res.
(1999) - et al.
GABAergic and glycinergic inhibitory mechanisms in the lamprey respiratory control
Brain Res.
(2006) - et al.
Neural mechanisms underlying respiratory rhythm generation in the lamprey
Respir. Physiol. Neurobiol.
(2016) - et al.
Central chemoreceptor drive to breathing in unanesthetized toads, Bufo paracnemis
Respir. Physiol.
(1992)
Branchial chemoreceptors mediate ventilatory responses to hypercapnic acidosis in channel catfish
Compar. Biochem. Physiol. – Mol. Integr. Physiol.
Learning in simple systems
Curr. Opin. Neurobiol.
Primordial respiratory-like rhythm generation in the vertebrate embryo
Trends Neurosci.
Prenatal development of central rhythm generation
Respir. Physiol. Neurobiol.
Blockade of NMDA receptor-channels by MK-801 alters breathing in adult rats
Brain Res.
The contribution of endogenous glutamatergic input in the ventral respiratory column to respiratory rhythm
Respir. Physiol. Neurobiol.
Depolarization and stimulation of neurons in nucleus tractus solitarii by carbon dioxide does not require chemical synaptic input
Neuroscience
pH regulation and proton signalling by glial cells
Prog. Neurobiol.
Neuromodulation and the orchestration of the respiratory rhythm
Respir. Physiol. Neurobiol.
ATP, glia and central respiratory control
Respir. Physiol. Neurobiol.
Development and pH sensitivity of the respiratory rhythm of fetal mice in vitro
Neuroscience
Nucleus isthmi and control of breathing in amphibians
Respir. Physiol. Neurobiol.
Control of breathing in anuran amphibians
Comp. Biochem. Physiol. A Mol. Integr. Physiol.
The locus coeruleus and central chemosensitivity
Respir. Physiol. Neurobiol.
Control of ventilation in the hypercapnic skate Raja ocellata: I. Blood and extradural fluid
Respir. Physiol.
Biological pattern generation: the cellular and computational logic of networks in motion
Neuron
The retrotrapezoid nucleus: central chemoreceptor and regulator of breathing automaticity
Trends Neurosci.
Apneusis follows disruption of NMDA-type glutamate receptors in vagotomized ground squirrels
Respir. Physiol. Neurobiol.
The presence of free D-serine in rat brain
FEBS Lett.
Extracellular concentration of endogenous free D-serine in the rat brain as revealed by in vivo microdialysis
Neuroscience
D-Serine: a key to synaptic plasticity?
Int. J. Biochem. Cell Biol.
TRP channels are involved in mediating hypercapnic Ca2+ responses in rat glia-rich medullary cultures independent of extracellular pH
Cell Calcium
Gene duplication: past, present and future
Semin. Cell Dev. Biol.
Levels of D-serine in the brain and peripheral organs of serine racemase (Srr) knock-out mice
Neurochem. Int.
Roles of P2 receptors in glial cells: focus on astrocytes
Purinergic Signal.
Glycine activated ion channel subunits encoded by ctenophore glutamate receptor genes
Proc. Natl. Acad. Sci. U. S. A.
Central ventilatory control in the South American lungfish, Lepidosiren paradoxa: contributions of pH and CO2
J. Comp. Physiol. B Biochem. Syst. Environ. Physiol.
Respiratory rhythm generation: triple oscillator hypothesis
F1000Research
A novel excitatory network for the control of breathing
Nature
Synaptically released acetylcholine evokes Ca2+ elevations in astrocytes in hippocampal slices
J. Neurosci.
Glial and neuronal control of brain blood flow
Nature
Respiratory behaviour, oxygen consumption and relative dependence on aerial respiration in the African lungfish (Protopterus annectens, owen) and an air-breathing teleost (Clarias lazera, C.)
Hydrobiologia
D-serine and serine racemase are localized to neurons in the adult mouse and human forebrain
Cell. Mol. Neurobiol.
Long-term potentiation and the ageing brain
Philos. Trans. R. Soc. Lond. B Biol. Sci.
D-serine released by astrocytes in brainstem regulates breathing response to CO2 levels
Nat. Commun.
Immunogold detection of L-glutamate and D-serine in small synaptic-like microvesicles in adult hippocampal astrocytes
Cereb. Cortex
Group I and II metabotropic glutamate receptors modulate respiratory activity in the lamprey
Eur. J. Neurosci.
Effect of temperature on central chemical control of ventilation in the alligator Alligator mississippiensis
J. Exp. Biol.
On the role of voltage-dependent calcium channels in calcium signaling of astrocytes in situ
J. Neurosci.
Functional characterization of a potassium-selective prokaryotic glutamate receptor
Nature
Cited by (3)
Prelude Special Issue: Breathing and Evolution
2022, Respiratory Physiology and NeurobiologyMicrobiome Metabolome Brain Vagus Nerve Circuit in Disease and Recovery
2023, Microbiome Metabolome Brain Vagus Nerve Circuit in Disease and Recovery
- 1
Indicates that authors contributed in similar way.