Ganglionic GFAP+ glial Gq-GPCR signaling enhances heart functions in vivo
Alison Xiaoqiao Xie, Jakovin J. Lee, Ken D. McCarthy
Alison Xiaoqiao Xie, Jakovin J. Lee, Ken D. McCarthy
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Research Article Cardiology Neuroscience

Ganglionic GFAP+ glial Gq-GPCR signaling enhances heart functions in vivo

Abstract

The sympathetic nervous system (SNS) accelerates heart rate, increases cardiac contractility, and constricts resistance vessels. The activity of SNS efferent nerves is generated by a complex neural network containing neurons and glia. Gq G protein–coupled receptor (Gq-GPCR) signaling in glial fibrillary acidic protein–expressing (GFAP+) glia in the central nervous system supports neuronal function and regulates neuronal activity. It is unclear how Gq-GPCR signaling in GFAP+ glia affects the activity of sympathetic neurons or contributes to SNS-regulated cardiovascular functions. In this study, we investigated whether Gq-GPCR activation in GFAP+ glia modulates the regulatory effect of the SNS on the heart; transgenic mice expressing Gq-coupled DREADD (designer receptors exclusively activated by designer drugs) (hM3Dq) selectively in GFAP+ glia were used to address this question in vivo. We found that acute Gq-GPCR activation in peripheral GFAP+ glia significantly accelerated heart rate and increased left ventricle contraction. Pharmacological experiments suggest that the glial-induced cardiac changes were due to Gq-GPCR activation in satellite glial cells within the sympathetic ganglion; this activation led to increased norepinephrine (NE) release and beta-1 adrenergic receptor activation within the heart. Chronic glial Gq-GPCR activation led to hypotension in female Gfap-hM3Dq mice. This study provides direct evidence that Gq-GPCR activation in peripheral GFAP+ glia regulates cardiovascular functions in vivo.

Authors

Alison Xiaoqiao Xie, Jakovin J. Lee, Ken D. McCarthy

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Figure 4

CNO-induced changes in cardiac functions are due to hM3Dq activation in peripheral glial cells, likely ganglionic SGCs.

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CNO-induced changes in cardiac functions are due to hM3Dq activation in ...
(A) AAV8-GFAP-GCaMP6–expressing astrocytes in visual cortex visualized through chronic polished window using 2-photon imaging before (left) and after (right) CNO i.p. injection in Gfap-hM3Dq mice (original magnification, 60×; scale bars: 40 μm). (B) Intracellular Ca2+ activity in cortical astrocytes in response to CNO i.p. administration, with or without i.p. trospium chloride injection (7 cells per condition, 2 repeats). (C) Trospium chloride, when administrated i.p., abolished CNO-induced increases in tachycardia (2-way ANOVA, n = 8–11 for each group; ***P < 0.0001, interaction between saline-treated Gfap-hM3Dq mice and littermate controls; ###P < 0.0001, interaction between saline- and trospium-treated Gfap-hM3Dq mice). (D) A cocktail of ganglionic blockers decreased baseline heart rates and blocked prazosin-induced tachycardia in both Gfap-hM3Dq and littermate control mice (n = 8–9 for each group). (E) The cocktail of ganglionic blockers did not block CNO-induced tachycardia in Gfap-hM3Dq mice (2-way ANOVA, ***P < 0.0001, interaction between blocker-treated Gfap-hM3Dq mice and littermate controls, n = 8–10 for each group). (F) CNO administration (0.5 mg/kg, s.c.) led to increases in heart rate in Gfap-hM3Dq+/–::Cx43–/–/Cx30–/– mice (n = 6), Gfap-hM3Dq+/–::d/nSNARE+/– mice (n = 3), Gfap-hM3Dq+/–::A1R–/– mice (n = 3), and Gfap-hM3Dq+/–::A2aR–/– mice (n = 3). Perturbing purinergic signaling with selective antagonists failed to block CNO-induced tachycardia in Gfap-hM3Dq mice; antagonists included P2X3 and P2X2/3 receptor antagonist (A-317491; n = 3) and adenosine A1 receptor antagonist (DPCPX; n = 3). Pre-block using nonselective P2 purinergic antagonist reduced but did not abolish CNO-induced tachycardia (PPADs; Mann-Whitney U test, *P < 0.01, n = 3). (G) Schematic model for CNO-induced, SNS-regulated cardiac changes in vivo in Gfap-hM3Dq mice.