Dataset Information

Astrocytes exhibit diverse Ca²⁺ changes at subcellular domains during brain aging.

ABSTRACT: Astrocytic Ca²⁺ transients are essential for astrocyte integration into neural circuits. These Ca²⁺ transients are primarily sequestered in subcellular domains, including primary branches, branchlets and leaflets, and endfeet. In previous studies, it suggests that aging causes functional defects in astrocytes. Until now, it was unclear whether and how aging affects astrocytic Ca²⁺ transients at subcellular domains. In this study, we combined a genetically encoded Ca²⁺ sensor (GCaMP6f) and in vivo two-photon Ca²⁺ imaging to determine changes in Ca²⁺ transients within astrocytic subcellular domains during brain aging. We showed that aging increased Ca²⁺ transients in astrocytic primary branches, higher-order branchlets, and terminal leaflets. However, Ca²⁺ transients decreased within astrocytic endfeet during brain aging, which could be caused by the decreased expressions of Aquaporin-4 (AQP4). In addition, aging-induced changes of Ca²⁺ transient types were heterogeneous within astrocytic subcellular domains. These results demonstrate that the astrocytic Ca²⁺ transients within subcellular domains are affected by aging differently. This finding contributes to a better understanding of the physiological role of astrocytes in aging-induced neural circuit degeneration.

SUBMITTER: Ding F

PROVIDER: S-EPMC9650392 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Astrocytes exhibit diverse Ca2+ changes at subcellular domains during brain aging.

Ding Fusheng F Liang Shanshan S Li Ruijie R Yang Zhiqi Z He Yong Y Yang Shaofan S Duan Qingtian Q Zhang Jianxiong J Lyu Jing J Zhou Zhenqiao Z Huang Mingzhu M Wang Haoyu H Li Jin J Yang Chuanyan C Wang Yuxia Y Gong Mingyue M Chen Shangbin S Jia Hongbo H Chen Xiaowei X Liao Xiang X Fu Ling L Zhang Kuan K

Frontiers in aging neuroscience 20221028

Astrocytic Ca2+ transients are essential for astrocyte integration into neural circuits. These Ca2+ transients are primarily sequestered in subcellular domains, including primary branches, branchlets and leaflets, and endfeet. In previous studies, it suggests that aging causes functional defects in astrocytes. Until now, it was unclear whether and how aging affects astrocytic Ca2+ transients at subcellular domains. In this study, we combined a genetically encoded ...[more]

PMID: 36389078

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Project description:Spontaneous Ca2+-release events (SCaEs) from the sarcoplasmic reticulum play crucial roles in the initiation of cardiac arrhythmias by promoting triggered activity. However, the subcellular determinants of these SCaEs remain incompletely understood. Structural differences between atrial and ventricular cardiomyocytes, e.g., regarding the density of T-tubular membrane invaginations, may influence cardiomyocyte Ca2+-handling and the distribution of cardiac ryanodine receptors (RyR2) has recently been shown to undergo remodeling in atrial fibrillation. These data suggest that the subcellular distribution of Ca2+-handling proteins influences proarrhythmic Ca2+-handling abnormalities. Here, we employ computational modeling to provide an in-depth analysis of the impact of variations in subcellular RyR2 and L-type Ca2+-channel distributions on Ca2+-transient properties and SCaEs in a human atrial cardiomyocyte model. We incorporate experimentally observed RyR2 expression patterns and various configurations of axial tubules in a previously published model of the human atrial cardiomyocyte. We identify an increased SCaE incidence for larger heterogeneity in RyR2 expression, in which SCaEs preferentially arise from regions of high local RyR2 expression. Furthermore, we show that the propagation of Ca2+ waves is modulated by the distance between RyR2 bands, as well as the presence of experimentally observed RyR2 clusters between bands near the lateral membranes. We also show that incorporation of axial tubules in various amounts and locations reduces Ca2+-transient time to peak. Furthermore, selective hyperphosphorylation of RyR2 around axial tubules increases the number of spontaneous waves. Finally, we present a novel model of the human atrial cardiomyocyte with physiological RyR2 and L-type Ca2+-channel distributions that reproduces experimentally observed Ca2+-handling properties. Taken together, these results significantly enhance our understanding of the structure-function relationship in cardiomyocytes, identifying that RyR2 and L-type Ca2+-channel distributions have a major impact on systolic Ca2+ transients and SCaEs.

Dataset Information

Astrocytes exhibit diverse Ca²⁺ changes at subcellular domains during brain aging.

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Astrocytes exhibit diverse Ca<sup>2+</sup> changes at subcellular domains during brain aging.

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