Activation of Astrocytes in the Persistence of Post-hypoxic Respiratory Augmentation.

Isato Fukushi,Mieczyslaw Pokorski,Hiroshi Onimaru,Akito Nakao,Yasumasa Okada,Yosuke Kono,Masashi Yoshizawa,Yohei Hasebe,Yasuo Mori,Kotaro Takeda

doi:10.3389/fphys.2021.757731

Abstract

Acute hypoxia increases ventilation. After cessation of hypoxia loading, ventilation decreases but remains above the pre-exposure baseline level for a time. However, the mechanism of this post-hypoxic persistent respiratory augmentation (PHRA), which is a short-term potentiation of breathing, has not been elucidated. We aimed to test the hypothesis that astrocytes are involved in PHRA. To this end, we investigated hypoxic ventilatory responses by whole-body plethysmography in unanesthetized adult mice. The animals breathed room air, hypoxic gas mixture (7% O2, 93% N2) for 2min, and again room air for 10min before and after i.p. administration of low (100mg/kg) and high (300mg/kg) doses of arundic acid (AA), an astrocyte inhibitor. AA suppressed PHRA, with the high dose decreasing ventilation below the pre-hypoxic level. Further, we investigated the role of the astrocytic TRPA1 channel, a putative ventilatory hypoxia sensor, in PHRA using astrocyte-specific Trpa1 knockout (asTrpa1−/−) and floxed Trpa1 (Trpa1f/f) mice. In both Trpa1f/f and asTrpa1−/− mice, PHRA was noticeable, indicating that the astrocyte TRPA1 channel was not directly involved in PHRA. Taken together, these results indicate that astrocytes mediate the PHRA by mechanisms other than TRPA1 channels that are engaged in hypoxia sensing.

Highlights

We found that the presence of active astrocytes is indispensable for the expression of PHRA, but their action is mediated by mechanisms other than transient receptor potential ankyrin 1 (TRPA1) channels
We examined the role of astrocyte TRPA1 channels in hypoxic ventilatory response (HVR) and PHRA using astrocyte-specific Trpa1 knockout mice
This study investigated the role of astrocytes in the PHRA, representing short-term potentiation of respiration

Summary

Introduction

The poststimulus overshoot in ventilatory activity may even go above the stimulus level as is evident in the acute hypoxic ventilatory response (HVR) to static exercise, with the mechanism ascribed to the interaction with the cardiovascular brain control or rapid release of the volitional hypothalamic control over sustained muscle tension (Pokorski et al, 1990). There are plastic interactions in relay circuits of hypoxic stimulus between peripheral chemoreceptors, among which carotid body chemoreceptors are most engaged in creating the HVR, and brain respiratory control pathways (Pamenter and Powell, 2016). That feature has been unraveled in adaptive plasticity to chronic hypoxia but is plausibly present in repeat acute hypoxic episodes characteristic of sleep apnea syndrome, the disease that distinctly affects brain function and increases chemoreflex sensitivity (Prabhakar, 2016)

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