Organotypic slice cultures containing the preBötzinger complex generate respiratory-like rhythms

Key pointsr The paratrigeminal respiratory group (pTRG) is responsible for the respiratory pattern generation in the lamprey.r The role of ATP and astrocytes, known to control respiratory activity in mammals, was investigated in the lamprey respiratory network.r ATP microinjected into the pTRG induces a biphasic response consisting of marked increases in respiratory frequency mediated by P2X receptors followed by a decrease in the respiratory motor output due to the ATP metabolite adenosine.r We provide evidence that astrocytes are involved in the genesis of the normal respiratory pattern, ATP-induced responses and acidification-induced increases of the respiratory activity.r The function of astrocytes in rhythmic networks appears to be phylogenetically conserved. AbstractThe role of ATP and astrocytes in respiratory rhythm modulation has been recently investigated in neonatal rodents. However, no information on the role of ATP and astrocytes within the respiratory network of the lamprey is available, particularly within the paratrigeminal respiratory group (pTRG), the proposed respiratory central pattern generator. To address these issues, the present study was carried out on isolated brainstems of the adult lamprey. Bath application of ATP caused marked increases in respiratory frequency followed by decreases in the respiratory motor output, mediated by the ATP metabolite adenosine at the level of the pTRG. Bath applications and microinjections of agonists and antagonists of purinergic receptors showed that ATP increased respiratory activity through an action on pTRG P2X receptors. To disclose the respiratory role of astrocytes, we used bath application of the gliotoxin aminoadipic acid, which dramatically depressed the respiratory motor output that, however, promptly recovered following glutamine application. Furthermore, the excitatory responses to ATP-γ-S (a non-hydrolysable ATP analogue), but not to substance P, microinjected into the pTRG, were abolished. Finally, we also demonstrated that acidification-induced increases in respiratory activity were ATP-independent, but mediated by the astrocytes' glutamate-glutamine cycle. The results show for the first time that ATP and especially astrocytes strongly contribute to the modulation of the lamprey respiratory pattern. Their role in the modulation or maintenance of rhythmic neuronal activities appears to be phylogenetically conserved.

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“…; Phillips et al . ), thus raising the possibility that astrocytes have an active role in respiratory rhythm generation.…”

Section: Discussionmentioning

confidence: 99%

ATP and astrocytes play a prominent role in the control of the respiratory pattern generator in the lamprey

Cinelli

Iovino

Mutolo

2017

The Journal of Physiology

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“…In the present study, we utilized organotypic brainstem slice cultures ( Forsberg et al, 2016 ; Phillips et al, 2016 ) of B6.Cg-Tg(hGFAP-tTA:: tetO-MrgA1)1 Kdmc/Mmmh mice (GFAP MrgA1+ ) in which green fluorescent protein (GFP) and the MrgA1 receptor (MrgA1R, encoded by Mrgpra1 ) were expressed under control of the promoter for glial fibrillary acidic protein (GFAP), a generally used marker for astrocytes ( Brenner et al, 1994 ). The MrgA1R is an endogenous G q -coupled receptor that is normally not expressed in the brain.…”

Section: Introductionmentioning

confidence: 99%

Astrocytes release prostaglandin E2 to modify respiratory network activity

Forsberg

Ringstedt

Herlenius

2017

eLife

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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 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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“…In the present study, we utilized organotypic brainstem slice cultures (Forsberg et al, 2016;Phillips et al, 2016) of B6.Cg-Tg(hGFAP-tTA:: tetO-MrgA1)1…”

Section: Introductionmentioning

confidence: 99%

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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Organotypic slice cultures containing the preBötzinger complex generate respiratory-like rhythms

Cited by 15 publications

References 30 publications

ATP and astrocytes play a prominent role in the control of the respiratory pattern generator in the lamprey

ATP and astrocytes play a prominent role in the control of the respiratory pattern generator in the lamprey

Astrocytes release prostaglandin E2 to modify respiratory network activity

Astrocytes release prostaglandin E2 to modify respiratory network activity

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