Mechanisms of CO<sub>2</sub>/H<sup>+</sup>Sensitivity of Astrocytes

Turovsky, Egor A.; Theparambil, Shefeeq M.; Kasymov, Vitaliy; Deitmer, Joachim W.; Arroyo, Ana Gutierrez del; Ackland, Gareth L.; Corneveaux, Jason J.; Allen, April N.; Huentelman, Matthew J.; Kasparov, Sergey; Marina, Nephtalı́; Gourine, Alexander V.

doi:10.1523/jneurosci.1281-16.2016

Cited by 102 publications

(73 citation statements)

References 35 publications

(8 reference statements)

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“…Our results, together with the previous study (Forsberg et al, 2016), strongly suggest that the release of gliotransmitters is the main signaling system. This is in accordance with the findings of other investigators Huckstepp et al, 2010;Turovsky et al, 2016). Specifically, we observed that almost half of the cells in the pFRG/RTN network were astrocytes and that these astrocytes could entrain the neuronal The following source data is available for figure 3:…”

Section: Resultssupporting

confidence: 92%

Astrocytes release prostaglandin E2 to modify respiratory network activity

Forsberg

Ringstedt

Herlenius

2017

Preprint

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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.

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Section: Resultssupporting

confidence: 92%

Astrocytes release prostaglandin E2 to modify respiratory network activity

Forsberg

Ringstedt

Herlenius

2017

Preprint

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“…In contrast, neocortical astrocytes, which are able to sense CO 2 increasing their intracellular calcium concentration 5 , were unresponsive in terms of d -serine and glutamate release. Whether neocortical astrocytes use similar mechanisms to those described in rostral brainstem astrocytes 34 to sense CO 2 is an open question. Our results indicate that medullary brainstem astrocytes differ from cortical astrocytes, at least, in the specific cellular response triggered by chemosensitive stimulation.…”

Section: Discussionmentioning

confidence: 99%

D-serine released by astrocytes in brainstem regulates breathing response to CO2 levels

et al. 2017

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Central chemoreception is essential for adjusting breathing to physiological demands, and for maintaining CO2 and pH homeostasis in the brain. CO2-induced ATP release from brainstem astrocytes stimulates breathing. NMDA receptor (NMDAR) antagonism reduces the CO2-induced hyperventilation by unknown mechanisms. Here we show that astrocytes in the mouse caudal medullary brainstem can synthesize, store, and release d-serine, an agonist for the glycine-binding site of the NMDAR, in response to elevated CO2 levels. We show that systemic and raphe nucleus d-serine administration to awake, unrestrained mice increases the respiratory frequency. Application of d-serine to brainstem slices also increases respiratory frequency, which was prevented by NMDAR blockade. Inhibition of d-serine synthesis, enzymatic degradation of d-serine, or the sodium fluoroacetate-induced impairment of astrocyte functions decrease the basal respiratory frequency and the CO2-induced respiratory response in vivo and in vitro. Our findings suggest that astrocytic release of d-serine may account for the glutamatergic contribution to central chemoreception.

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“…Further, brainstem astrocytes respond to changes in blood gas levels ( Angelova et al, 2015 ), especially in the chemosensitive region the parafacial respiratory group/retrotrapezoid nucleus (pFRG/RTN) ( Huckstepp et al, 2010 ). During the hypercapnic response, carbon dioxide (CO 2 ) causes ATP release from astrocytes ( Fukuda et al, 1978 ; Erlichman et al, 2010 ; Gourine et al, 2010 ; Huckstepp et al, 2010 ; Turovsky et al, 2015 ; Turovsky et al, 2016 ), increasing inspiratory frequency ( Lorier et al, 2007 ; Gourine et al, 2010 ). We recently provided evidence that CO 2 also elicits a gap junction-dependent release of PGE2 ( Forsberg et al, 2016 ), increasing the signaling frequency of the pFRG/RTN ( Forsberg et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Astrocytes release prostaglandin E2 to modify respiratory network activity

Forsberg

Ringstedt

Herlenius

2017

eLife

View full text Add to dashboard Cite

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 preBötzinger complex and pFRG/RTN. However, neurons in the preBötC 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.

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Mechanisms of CO₂/H⁺Sensitivity of Astrocytes

Cited by 102 publications

References 35 publications

Astrocytes release prostaglandin E2 to modify respiratory network activity

Astrocytes release prostaglandin E2 to modify respiratory network activity

D-serine released by astrocytes in brainstem regulates breathing response to CO2 levels

Astrocytes release prostaglandin E2 to modify respiratory network activity

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Mechanisms of CO2/H+Sensitivity of Astrocytes

Cited by 102 publications

References 35 publications

Astrocytes release prostaglandin E2 to modify respiratory network activity

Astrocytes release prostaglandin E2 to modify respiratory network activity

D-serine released by astrocytes in brainstem regulates breathing response to CO2 levels

Astrocytes release prostaglandin E2 to modify respiratory network activity

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Mechanisms of CO₂/H⁺Sensitivity of Astrocytes