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

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dc.contributor.authorMizuno, Grace O.en
dc.contributor.authorWang, Yinxueen
dc.contributor.authorShi, Guilaien
dc.contributor.authorWang, Yizhien
dc.contributor.authorSun, Junqingen
dc.contributor.authorPapadopoulos, Steliosen
dc.contributor.authorBroussard, Gerard J.en
dc.contributor.authorUnger, Elizabeth K.en
dc.contributor.authorDeng, Wenbinen
dc.contributor.authorWeick, Jasonen
dc.contributor.authorBhattacharyya, Anitaen
dc.contributor.authorChen, Chao-Yinen
dc.contributor.authorYu, Guoqiangen
dc.contributor.authorLooger, Loren L.en
dc.contributor.authorTian, Linen
dc.contributor.departmentElectrical and Computer Engineeringen
dc.date.accessioned2019-05-29T16:26:02Zen
dc.date.available2019-05-29T16:26:02Zen
dc.date.issued2018-07-10en
dc.description.abstractDown 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 neuronastrocyte interplay in a fully recapitulated HSA21 trisomy cellular model differentiated from DS-patientderived induced pluripotent stem cells (iPSCs). By combining calciumimaging 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.en
dc.description.notesThis work was supported by the Hartwell Foundation Individual Biomedical Award (L.T.), NIH DP2MH107056 (L.T.), NIH R21NS095325 (L.T.), NIH R01MH110504 (L.T. and G.Y.), NSF1750931 (G.Y.), NIH R03 HD064880 (A.B.), National Institute of General Medical Sciences (NIGMS) 1P20GM109089-01A1 (J.W.), National Institute of Neurological Disorders and Stroke (NINDS) R21NS093442-01 and NSF7566685 (J.W.), and National Institute on Deafness and Other Communication Disorders (INCD) R01HD09325 (W.D.). This project was supported by the University of California, Davis, Flow Cytometry Shared Resource Laboratory with technical assistance from Ms. Bridget McLaughlin and Mr. Jonathan Van Dyke. We would like to give special thanks to Dr. Bart Borghuis for generously sharing the FluoAnalyzer codes, Dr. Karen Zito for critical input, Dr. Brett Mensh for critical discussions, and Lisa Makhoul for editorial assistance.en
dc.description.sponsorshipHartwell Foundation Individual Biomedical Award; NIH [DP2MH107056, R21NS095325, R01MH110504, NSF1750931, R03 HD064880]; National Institute of General Medical Sciences (NIGMS) [1P20GM109089-01A1]; National Institute of Neurological Disorders and Stroke (NINDS) [R21NS093442-01, NSF7566685]; National Institute on Deafness and Other Communication Disorders (INCD) [R01HD09325]; University of California, Davisen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1016/j.celrep.2018.06.033en
dc.identifier.issn2211-1247en
dc.identifier.issue2en
dc.identifier.pmid29996097en
dc.identifier.urihttp://hdl.handle.net/10919/89632en
dc.identifier.volume24en
dc.language.isoenen
dc.publisherElsevieren
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectMotor-Neuronsen
dc.subjectMurine Modelen
dc.subjectDeficitsen
dc.subjectDysfunctionen
dc.subjectReleaseen
dc.subjectDiseaseen
dc.subjectProteinen
dc.subjectMouseen
dc.subjectApoptosisen
dc.subjectAdenosineen
dc.titleAberrant Calcium Signaling in Astrocytes Inhibits Neuronal Excitability in a Human Down Syndrome Stem Cell Modelen
dc.title.serialCell Reportsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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Scholarly Works, Electrical and Computer Engineering
Destination Area: Adaptive Brain and Behavior (ABB)