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

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

doi:10.3389/fphys.2021.757731

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

Front Physiol. 2021 Oct 8:12:757731. doi: 10.3389/fphys.2021.757731. eCollection 2021.

Authors

Isato Fukushi^{1

2}, Kotaro Takeda^{2

3}, Mieczyslaw Pokorski^{4

5}, Yosuke Kono^{2

6}, Masashi Yoshizawa^{2

6}, Yohei Hasebe^{2

6}, Akito Nakao⁷, Yasuo Mori⁷, Hiroshi Onimaru⁸, Yasumasa Okada²

Affiliations

¹ Faculty of Health Sciences, Uekusa Gakuen University, Chiba, Japan.
² Clinical Research Center, Murayama Medical Center, Musashimurayama, Japan.
³ Faculty of Rehabilitation, School of Healthcare, Fujita Health University, Toyoake, Japan.
⁴ Institute of Health Sciences, University of Opole, Opole, Poland.
⁵ Faculty of Health Sciences, The Jan Dlugosz University in Czestochowa, Czestochowa, Poland.
⁶ Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
⁷ Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan.
⁸ Department of Physiology, Showa University School of Medicine, Tokyo, Japan.

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 (Trpa1 ^f/f) mice. In both Trpa1 ^f/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.

Keywords: TRPA1; arundic acid; astrocyte; hypoxia; plasticity; post-hypoxic respiratory augmentation; respiratory control; short-term potentiation.