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Cell Rep. 2018 Jul 10;24(2):355-365. doi: 10.1016/j.celrep.2018.06.033.

Aberrant Calcium Signaling in Astrocytes Inhibits Neuronal Excitability in a Human Down Syndrome Stem Cell Model.

Author information

1
Department of Biochemistry and Molecular Medicine, Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA, USA.
2
Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
3
Department of Pharmacology, University of California, Davis, Davis, CA, USA.
4
Department of Biochemistry and Molecular Medicine, Shriner's Hospital, University of California, Davis, Davis, CA, USA.
5
Department of Neuroscience, University of New Mexico, Albuquerque, NM, USA.
6
Waisman Center, University of Wisconsin, Madison, Madison, WI, USA.
7
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA.
8
Department of Biochemistry and Molecular Medicine, Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA, USA. Electronic address: lintian@ucdavis.edu.

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.

KEYWORDS:

Down syndrome; S100B; astrocyte-neuron interaction; astrocytes; calcium imaging; human IPSCs

PMID:
29996097
PMCID:
PMC6631348
DOI:
10.1016/j.celrep.2018.06.033
[Indexed for MEDLINE]
Free PMC Article

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