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

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2018 Jul 12

PMID 29996097

Citations 29

Authors

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

Soon will be listed here.

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 (IP) 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.

Citing Articles

Astrocytic Alterations and Dysfunction in Down Syndrome: Focus on Neurogenesis, Synaptogenesis, and Neural Circuits Formation.

Uguagliati B, Grilli M Cells. 2025; 13(24.

PMID: 39768129 PMC: 11674571. DOI: 10.3390/cells13242037.

Consequences of trisomy 21 for brain development in Down syndrome.

Russo M, Sousa A, Bhattacharyya A Nat Rev Neurosci. 2024; 25(11):740-755.

PMID: 39379691 PMC: 11834940. DOI: 10.1038/s41583-024-00866-2.

A dynamic in vitro model of Down syndrome neurogenesis with trisomy 21 gene dosage correction.

Bansal P, Banda E, Glatt-Deeley H, Stoddard C, Linsley J, Arora N Sci Adv. 2024; 10(23):eadj0385.

PMID: 38848354 PMC: 11160455. DOI: 10.1126/sciadv.adj0385.

Single-nucleus RNA sequencing reveals cell type-specific transcriptome alterations of Down syndrome hippocampus using the Dp16 mouse model.

Zhou Z, Zhi C, Chen D, Cai Z, Jiang X Genes Genomics. 2023; 45(10):1305-1315.

PMID: 37548883 DOI: 10.1007/s13258-023-01433-2.

Robust induction of functional astrocytes using NGN2 expression in human pluripotent stem cells.

Berryer M, Tegtmeyer M, Binan L, Valakh V, Nathanson A, Trendafilova D iScience. 2023; 26(7):106995.

PMID: 37534135 PMC: 10391684. DOI: 10.1016/j.isci.2023.106995.

References

Sloan S, Barres B . Looks can be deceiving: reconsidering the evidence for gliotransmission. Neuron. 2014; 84(6):1112-5. PMC: 4433290. DOI: 10.1016/j.neuron.2014.12.003. View

Wang X, Lou N, Xu Q, Tian G, Peng W, Han X . Astrocytic Ca2+ signaling evoked by sensory stimulation in vivo. Nat Neurosci. 2006; 9(6):816-23. DOI: 10.1038/nn1703. View

Ballestin R, Blasco-Ibanez J, Crespo C, Nacher J, Lopez-Hidalgo R, Gilabert-Juan J . Astrocytes of the murine model for Down Syndrome Ts65Dn display reduced intracellular ionic zinc. Neurochem Int. 2014; 75:48-53. DOI: 10.1016/j.neuint.2014.05.013. View

NEWMAN E . Propagation of intercellular calcium waves in retinal astrocytes and Müller cells. J Neurosci. 2001; 21(7):2215-23. PMC: 2409971. View

Bazargani N, Attwell D . Astrocyte calcium signaling: the third wave. Nat Neurosci. 2016; 19(2):182-9. DOI: 10.1038/nn.4201. View

Molofsky A, Krencik R, Krenick R, Ullian E, Ullian E, Tsai H . Astrocytes and disease: a neurodevelopmental perspective. Genes Dev. 2012; 26(9):891-907. PMC: 3347787. DOI: 10.1101/gad.188326.112. View

Khakh B, McCarthy K . Astrocyte calcium signaling: from observations to functions and the challenges therein. Cold Spring Harb Perspect Biol. 2015; 7(4):a020404. PMC: 4382738. DOI: 10.1101/cshperspect.a020404. View

Adair T . Growth regulation of the vascular system: an emerging role for adenosine. Am J Physiol Regul Integr Comp Physiol. 2005; 289(2):R283-R296. DOI: 10.1152/ajpregu.00840.2004. View

Kawamura Jr M, Kawamura M . Long-term facilitation of spontaneous calcium oscillations in astrocytes with endogenous adenosine in hippocampal slice cultures. Cell Calcium. 2011; 49(4):249-58. DOI: 10.1016/j.ceca.2011.02.009. View

10.

Chambers S, Fasano C, Papapetrou E, Tomishima M, Sadelain M, Studer L . Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol. 2009; 27(3):275-80. PMC: 2756723. DOI: 10.1038/nbt.1529. View

11.

Barger S, Wolchok S, Van Eldik L . Disulfide-linked S100 beta dimers and signal transduction. Biochim Biophys Acta. 1992; 1160(1):105-12. DOI: 10.1016/0167-4838(92)90043-d. View

12.

Nam H, McIver S, Hinton D, Thakkar M, Sari Y, Parkinson F . Adenosine and glutamate signaling in neuron-glial interactions: implications in alcoholism and sleep disorders. Alcohol Clin Exp Res. 2012; 36(7):1117-25. PMC: 3349794. DOI: 10.1111/j.1530-0277.2011.01722.x. View

13.

Vaarmann A, Gandhi S, Abramov A . Dopamine induces Ca2+ signaling in astrocytes through reactive oxygen species generated by monoamine oxidase. J Biol Chem. 2010; 285(32):25018-23. PMC: 2915737. DOI: 10.1074/jbc.M110.111450. View

14.

Turrigiano G . Homeostatic synaptic plasticity: local and global mechanisms for stabilizing neuronal function. Cold Spring Harb Perspect Biol. 2011; 4(1):a005736. PMC: 3249629. DOI: 10.1101/cshperspect.a005736. View

15.

Pasca A, Sloan S, Clarke L, Tian Y, Makinson C, Huber N . Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods. 2015; 12(7):671-8. PMC: 4489980. DOI: 10.1038/nmeth.3415. View

16.

Murray A, Letourneau A, Canzonetta C, Stathaki E, Gimelli S, Sloan-Bena F . Brief report: isogenic induced pluripotent stem cell lines from an adult with mosaic down syndrome model accelerated neuronal ageing and neurodegeneration. Stem Cells. 2015; 33(6):2077-84. PMC: 4737213. DOI: 10.1002/stem.1968. View

17.

Lee S, Yoon B, Berglund K, Oh S, Park H, Shin H . Channel-mediated tonic GABA release from glia. Science. 2010; 330(6005):790-6. DOI: 10.1126/science.1184334. View

18.

Koizumi S . Synchronization of Ca2+ oscillations: involvement of ATP release in astrocytes. FEBS J. 2009; 277(2):286-92. DOI: 10.1111/j.1742-4658.2009.07438.x. View

19.

Torres M, Garcia O, Tang C, Busciglio J . Dendritic spine pathology and thrombospondin-1 deficits in Down syndrome. Free Radic Biol Med. 2017; 114:10-14. PMC: 7185223. DOI: 10.1016/j.freeradbiomed.2017.09.025. View

20.

Busciglio J, Pelsman A, Wong C, Pigino G, Yuan M, Mori H . Altered metabolism of the amyloid beta precursor protein is associated with mitochondrial dysfunction in Down's syndrome. Neuron. 2002; 33(5):677-88. DOI: 10.1016/s0896-6273(02)00604-9. View