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 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.
Highlights
It has become evident that astrocytes are involved in respiratory behavior; electrically active astrocytes are present in the brainstem respiratory center the preBötzinger Complex (Grass, Pawlowski et al 2004) and exhibit rhythmic calcium (Ca2+) oscillations associated with the respiratory-related neuronal rhythm (Schnell, Fresemann et al 2011, Okada, Sasaki et al 2012)
Because prostaglandin E2 (PGE2) is released through gap junctions during hypercapnia, and since some astrocytes in the pFRG/RTN express the primary enzyme involved in PGE2 synthesis (Forsberg, Horn et al 2016), we hypothesized that hypercapnia induces astrocytes to release PGE2 in addition to ATP
Expression of green fluorescent protein (GFP) in the pFRG/RTN and preBötzinger Complex (preBötC) of the GFAPMrgA1+ mice was evident (Figure 1), and GFP was co-localized with GFAP immunolabeling (Figure 1b and h, n = 11 slices; see Table 1 for the number of times each experiment was conducted)
Summary
It has become evident that astrocytes are involved in respiratory behavior; electrically active astrocytes are present in the brainstem respiratory center the preBötzinger Complex (preBötC) (Grass, Pawlowski et al 2004) and exhibit rhythmic calcium (Ca2+) oscillations associated with the respiratory-related neuronal rhythm (Schnell, Fresemann et al 2011, Okada, Sasaki et al 2012). Acting via EP3 receptors, prostaglandin E2 (PGE2) alters respiratory network activity by inhibiting signaling frequency in the preBötC while increasing it in the pFRG/RTN (Forsberg, Horn et al 2016). To investigate the role of astrocytes in respiratory rhythm-generating networks and determine whether astrocytes release PGE2, we utilized organotypic brainstem slice cultures (Forsberg, Horn et al 2016, Phillips, Herly et al 2016) of B6.Cg-Tg(hGFAP-tTA:: tetO-
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