Phylogenetically persistent purinergic modulation of central pattern generators for breathing in lamprey and mammals

Vertebrate behaviours are produced by neuroglial networks that evolved from a common set of ancestral (homologous) traits, as well as unique specializations that created opportunities for new behaviours and exploitation of novel environments. Discriminating ancestral network traits from unique specializations that arose along specific lineages is a daunting, often impossible, task but the promise of unveiling fundamental organizational principles and mechanisms remains powerful motivation for evolutionary/comparative studies. In this issue of The Journal of Physiology, Cinelli et al. (2017) show common homeostatic roles for purinergic signalling and neuroglia in the paratrigeminal respiratory pattern generating network (paratrigeminal respiratory group, pTRG) of the water-breathing lamprey, one of the most primitive extant vertebrates, and the preBötzinger complex (preBötC) inspiratory rhythm generating network of air-breathing mammals. The jawless lamprey usurped for gas exchange water currents that were originally generated to support filter feeding. The pTRG derived from rhombomeres 2 and 3 (pons) drives rhythmic contraction of pharyngeal (branchial) muscles, causing compression and active expiration of water followed by passive expansion (inspiration) that tidally ventilates the gill pouches (Ramirez et al. 2016). In mammals (at rest) the preBötC, a more caudal brainstem oscillator derived from rhombomeres 7–8 drives rhythmic contraction of axial (body wall) rather than pharyngeal muscles to produce breathing that for the first time in vertebrate phylogeny occurs via active inspiration and passive expiration (Ramirez et al. 2016). Despite the fact the networks responsible for generating breathing in lamprey and mammals do not appear to be homologous, Cinelli et al. show that two phylogenetically ancient components of brain networks, purinergic signalling and neuroglia, have common modulatory actions on vertebrate breathing networks. Evolution of neuroglia has been proposed as key for the evolution of complex nervous systems, i.e. that as neurons became increasingly specialized for signalling and integration progressive assumption of basic housekeeping/homeostasic functions by neuroglia was essential. Consistent with this, emergence of neuroglia coincides with the evolution of bilateral symmetry and centralization of the nervous system (in annelids and arthropods) (Parpura & Verkhratsky, 2012). Glial proliferation and diversity also correlate strongly with nervous system complexity; in fact recent data strongly suggest that astroglial function has expanded to include roles in signalling and local information processing. Despite this evolutionary elaboration, Cinelli et al. (2017) show that a hallmark of glial function, maintenance of metabolic homeostasis via supply of glutamine to neurons, persists throughout vertebrate evolution. Respiratory rhythm in lamprey was severely disrupted by the glial toxin l-2-aminoadipic acid, but restored by supplying glutamine, a glutamate precursor essential for proper neuronal function that is normally supplied by glia. Rhythmic inspiratory-related activity generated by preBötC-containing medullary slices from mammals (rodents) is similarly disrupted by glial toxins and restored by the addition of glutamine (Hulsmann et al. 2000). Cinelli et al. also demonstrate that, like the preBötC of rat and mouse (Gourine & Funk, 2017), the pTRG of lamprey responds to exogenous ATP with a biphasic response comprising an initial P2 receptor-mediated excitation followed by a secondary inhibition due to breakdown of ATP into adenosine and activation of P1 receptors (A1 subtype). In rodents, diverse ectonucleotidases degrade ATP into adenosine and are key factors shaping the response of the preBötC to ATP (Zwicker et al. 2011). Similar enzymes are also likely to be important in lamprey. Indeed the importance of the interaction between P2 receptor signalling, ectonucleotidases and P1 receptor signalling in determining the net actions of ATP on cellular/network function appears phylogenetically ancient. Cloning studies indicate that mammalian-like P2X receptors were present in primitive invertebrates, including amoeba, flatworms and even the green algae Ostreococcus (the smallest living eukaryote), and that metabotropic P2Y1 and P1 receptors and ectonucleotidases arose at a similar (perhaps slightly later) time. Thus, while purinergic systems have become more complex in vertebrates with ATP signalling through seven ionotropic P2X receptors and eight metabotropic P2Y receptors, and adenosine signalling through four metabotropic P1 receptors following degradation of ATP by diverse ectonucleotidases, the interaction between P2 and P1 receptor signalling appears to be a primordial feature of purinergic signalling that has remained relevant through evolution (Burnstock & Verkhratsky, 2009). The excitation of the lamprey pTRG by ATP also appears to involve glia. As seen previously in the preBötC of rat (Gourine & Funk, 2017), glial toxins in the lamprey disrupted neuroglial morphology and inhibited the ability of ATP to excite the pTRG without affecting the ability of the network to respond to the excitatory neuropeptide substance P. An important future objective will be to establish the physiological significance of this glial toxin-sensitive ATP excitation of the lamprey pTRG, i.e. under what conditions is ATP released endogenously? In mammals, astroglial ATP signalling plays an important role in the biphasic hypoxic ventilatory response, which comprises an initial carotid body-mediated increase in ventilation followed by a secondary depression. PreBötC astrocytes appear to contribute to this response by sensing hypoxia via a mitochondrial mechanism that causes vesicular release of ATP, activation of P2Y1 receptors on preBötC neurons and an increase in breathing that attenuates the secondary hypoxic respiratory depression (Gourine & Funk, 2017). Operation of a similar mechanism in lamprey is an attractive hypothesis given that ancestral organisms like the lamprey living in aquatic, O2-poor environments would be well served by a central hypoxia sensor. However, the ventilatory response of lamprey to hypoxia appears to be mediated by peripheral chemoreceptors, leaving a host of questions including the function of the ATP-mediated excitation of the lamprey pTRG. Perhaps it is the evolutionary substrate that gave rise to the astrocyte-mediated, purinergic, hypoxia-sensing mechanism that appears to operate in the mammalian preBötC (Gourine & Funk, 2017)? None declared. G.D.F. is supported by the Canadian Institutes of Health Research (no. 53085), the Natural Sciences and Engineering Research Council of Canada (no. 402532) and the Women and Children's Health Research Institute, University of Alberta.

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