Aberrant Calcium Signaling in Astrocytes Inhibits Neuronal Excitability in a Human Down Syndrome Stem Cell Model
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
Affiliations
Grace O. Mizuno
Department of Biochemistry and Molecular Medicine, Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA, USA
Yinxue Wang
Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
Guilai Shi
Department of Biochemistry and Molecular Medicine, Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA, USA
Yizhi Wang
Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
Junqing Sun
Department of Pharmacology, University of California, Davis, Davis, CA, USA
Stelios Papadopoulos
Department of Biochemistry and Molecular Medicine, Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA, USA
Gerard J. Broussard
Department of Biochemistry and Molecular Medicine, Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA, USA
Elizabeth K. Unger
Department of Biochemistry and Molecular Medicine, Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA, USA
Wenbin Deng
Department of Biochemistry and Molecular Medicine, Shriner’s Hospital, University of California, Davis, Davis, CA, USA
Jason Weick
Department of Neuroscience, University of New Mexico, Albuquerque, NM, USA
Anita Bhattacharyya
Waisman Center, University of Wisconsin, Madison, Madison, WI, USA
Chao-Yin Chen
Department of Pharmacology, University of California, Davis, Davis, CA, USA
Guoqiang Yu
Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA
Loren L. Looger
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA
Lin Tian
Department of Biochemistry and Molecular Medicine, Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA, USA; Corresponding author
Summary: 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. : To understand how Down syndrome (DS) affects neural networks, Mizuno et al. used a DS-patient-derived stem cell model and calcium imaging to investigate the functional defects of DS astrocytes and their effects on neuronal excitability. Their study reveals that DS astroglia exhibited more frequent spontaneous calcium fluctuations, which impair neuronal excitability. Keywords: Down syndrome, astrocytes, astrocyte-neuron interaction, human IPSCs, calcium imaging, S100B
