Astrocytes release prostaglandin E2 to modify respiratory network activity

Abstract

Previously (Forsberg et al., 2016), we revealed that prostaglandin E2 (PGE2), released during hypercapnic challenge, increases calcium oscillations in the chemosensitive parafacial respiratory group (pFRG/RTN). Here, we demonstrate that pFRG/RTN astrocytes are the PGE2 source. Two distinct astrocyte subtypes were found using transgenic mice expressing GFP and MrgA1 receptors in astrocytes. Although most astrocytes appeared dormant during time-lapse calcium imaging, a subgroup displayed persistent, rhythmic oscillating calcium activity. These active astrocytes formed a subnetwork within the respiratory network distinct from the neuronal network. Activation of exogenous MrgA1Rs expressed in astrocytes tripled astrocytic calcium oscillation frequency in both the preBö tzinger complex and pFRG/RTN. However, neurons in the preBö tC were unaffected, whereas neuronal calcium oscillatory frequency in pFRG/RTN doubled. Notably, astrocyte activation in pFRG/RTN triggered local PGE2 release and blunted the hypercapnic response. Thus, astrocytes play an active role in respiratory rhythm modulation, modifying respiratory-related behavior through PGE2 release in the pFRG/RTN.

Morphometric analysis of astrocytes in brainstem respiratory regions

“…Fine astrocytic processes are closely associated with pre‐ and post‐synaptic neurons to form tripartite synapses (Araque, Parpura, Sanzgiri, & Haydon, ; Halassa et al, ; Perea, Navarrete, & Araque, ; Santello, Calì, & Bezzi, ), potentially modulating synaptic signaling and plasticity. Astroglial signaling has been shown to modulate activities of autonomic and respiratory circuits in several regions of the brainstem containing functionally distinct neural networks including the preBötC (Forsberg et al, ; Sheikhbahaei et al, ), RTN (Erlichman & Leiter, ; Gourine et al, ; Huckstepp et al, ; Mulkey & Wenker, ; Wenker, Sobrinho, Takakura, Moreira, & Mulkey, ), rostral ventrolateral medulla (Marina et al, ) and NTS (Accorsi‐Mendonça, Zoccal, Bonagamba, & Machado, ; Funk et al, ). While it has been proposed that astrocytes may have neural circuit‐specific structural and functional properties (Chai et al, ), the morphological features of astrocytes residing in functionally distinct brainstem respiratory regions have not been examined.…”

“…Since glutamate-mediated transmission is critical for the generation of the inspiratory rhythm (Feldman et al, 2013;Hayes, Wang, & Del Negro, 2012;Koizumi et al, 2016;Koshiya & Smith, 1999), preBötC astrocytes could potentially modulate the activities of respiratory rhythm generating neurons via control of glutamate re-cycling (Hülsmann et al, 2000). In addition, preBötC astrocytes directly modulate inspiratory circuit activity through the release of gliotransmitters, particularly ATP/adenosine (Huxtable et al, 2009;Lorier et al, 2007;Rajani et al, 2017;Sheikhbahaei et al, 2018), prostaglandin E2 (Forsberg, Ringstedt, & Herlenius, 2017), and D-serine (Beltrán-Castillo et al, 2017). However, morphological arrangements of astrocytes that may reflect the complexity and functional significance of neuroglial interactions in respiratory regions and other brainstem areas have not been investigated.…”

Interdependent feedback regulation of breathing by the carotid bodies and the retrotrapezoid nucleus

“…Astrocyte depolarization may further enhance the acidification of the RTN region relative to that of the plasma via the phenomenon called depolarization-induced alkalization, thereby increasing the sensitivity of RTN neurons to changes in arterial pH. Astrocytes may also activate RTN neurons by releasing ATP, prostaglandin E2 or D-alanine Beltran-Castillo et al 2017;Forsberg et al 2017; see legend to Fig. 2C for additional references and further details regarding these mechanisms).…”

“…; Forsberg et al . ; see legend to Fig. C for additional references and further details regarding these mechanisms).…”

Advances in cellular and integrative control of oxygen homeostasis within the central nervous system

“…; Forsberg et al . ). Interestingly, the neuroglial interactions that seem to underlie //H + sensitivity in the central nervous system are strikingly similar to those that occur peripherally in the carotid bodies (Figs and ) (Kumar & Prabhakar, ).…”