Astrocytic contribution to glutamate-related central respiratory chemoreception in vertebrates

https://doi.org/10.1016/j.resp.2021.103744Get rights and content

Highlights

  • Central respiratory chemoreceptors play a key role in the respiratory homeostasis.

  • Glutamatergic transmission is involved as a main mechanism in central chemoreception.

  • Rostral or caudal brainstem astrocytes release ATP or D-serine in response to hypercapnia to activate the respiratory rhythm.

  • In primitive vertebrates, astrocytes contribute to modulate the respiratory rhythm and its response to acidosis.

  • Astrocytic glutamatergic contribution to the central respiratory chemoreception seems conserved along the vertebrate lineage.

Abstract

Central respiratory chemoreceptors play a key role in the respiratory homeostasis by sensing CO2 and H+ in brain and activating the respiratory neural network. This ability of specific brain regions to respond to acidosis and hypercapnia is based on neuronal and glial mechanisms. Several decades ago, glutamatergic transmission was proposed to be involved as a main mechanism in central chemoreception. However, a complete identification of mechanism has been elusive. At the rostral medulla, chemosensitive neurons of the retrotrapezoid nucleus (RTN) are glutamatergic and they are stimulated by ATP released by RTN astrocytes in response to hypercapnia. In addition, recent findings show that caudal medullary astrocytes in brainstem can also contribute as CO2 and H+ sensors that release D-serine and glutamate, both gliotransmitters able to activate the respiratory neural network. In this review, we describe the mammalian astrocytic glutamatergic contribution to the central respiratory chemoreception trying to trace in vertebrates the emergence of several components involved in this process.

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.

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