Aberrant calcium signaling in astrocytes inhibits neuronal excitability in a human Down syndrome stem cell model.

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Cell Reports. 2018 Jul 10;24(2):355-65. doi: 10.1101/247585

Aberrant calcium signaling in astrocytes inhibits neuronal excitability in a human Down syndrome stem cell model. Looger Lab

Tian L, Or G, Wang Y, Shi G, Wang Y, Sun J, Papadopoulos S, Broussard G, Unger E, Deng W, Weick J, Bhattacharyya A, Chen C, Yu G, Looger LL

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Abstract

Down syndrome (DS) is a genetic disorder that causes cognitive impairment. The staggering effects associated with an extra copy of human chromosome 21 (HSA21) complicates mechanistic understanding of DS pathophysiology. We examined the neuron-astrocyte interplay in a fully recapitulated HSA21 trisomy cellular model differentiated from DS-patient-derived induced pluripotent stem cells (iPSCs). By combining calcium imaging with genetic approaches, we discovered the functional defects of DS astroglia and their effects on neuronal excitability. Compared with control isogenic astroglia, DS astroglia exhibited more-frequent spontaneous calcium fluctuations, which reduced the excitability of co-cultured neurons. Furthermore, suppressed neuronal activity could be rescued by abolishing astrocytic spontaneous calcium activity either chemically by blocking adenosine-mediated signaling or genetically by knockdown of inositol triphosphate (IP3) receptors or S100B, a calcium binding protein coded on HSA21. Our results suggest a mechanism by which DS alters the function of astrocytes, which subsequently disturbs neuronal excitability.

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First published as a preprint in bioRxiv on January 14, 2018. https://doi.org/10.1101/247585

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Aberrant calcium signaling in astrocytes inhibits neuronal excitability in a human Down syndrome stem cell model.

Abstract

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