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

By Grace O. Mizuno, Yinxue Wang, Guilai Shi, Yizhi Wang, Junqing Sun, Stelios Papadopoulos, Gerard J. Broussard, Elizabeth K. Unger, Wenbin Deng, Jason Weick, Anita Bhattacharyya, Chao-Yin Chen, Guoqiang Yu, Loren L. Looger, Lin Tian

Posted 14 Jan 2018
bioRxiv DOI: 10.1101/247585 (published DOI: 10.1016/j.celrep.2018.06.033)

Down syndrome (DS) is a devastating genetic disorder causing severe cognitive impairment. The staggering array of effects associated with an extra copy of human chromosome 21 (HSA21) complicates mechanistic understanding of DS pathophysiology. We developed an in vitro system to examine the interplay of neurons and astrocytes in a fully recapitulated HSA21 trisomy model differentiated from DS patient-derived induced pluripotent stem cells (iPSCs). By combining calcium imaging with genetic approaches, we utilized this system to investigate the functional defects of DS astroglia and their effects on neuronal excitability. We found that, compared with control isogenic astroglia, DS astroglia exhibited more frequent spontaneous calcium fluctuations, which reduced the excitability of co-cultured neurons. DS astrocytes exerted this effect on both DS and healthy neurons. Neuronal activity could be rescued by abolishing astrocytic spontaneous calcium activity either chemically by blocking adenosine-mediated astrocyte-neuron signaling or genetically by knockdown of inositol triphosphate (IP3) receptors or S100β, a calcium binding protein coded on HSA21. Our results suggest a novel mechanism by which DS alters the function of astrocytes, which subsequently disturbs neuronal excitability. Furthermore, our study establishes an all optical neurophysiological platform for studying human neuron astrocyte interactions associated with neurological disorders.

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