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

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

doi:10.1016/j.celrep.2018.06.033

Cited by 44 publications

(42 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since mitochondrial function is the crucial contributor to ATP generation in mammalian cells, and ATP is essential to the maintenance of all fundamental cellular function in resting cells, (and even more so in dividing ones), one would expect that a significant impairment of cellular ATP synthesis would result in significant suppression of all fundamental cellular functions, including cellular division cell proliferation, maintenance of membrane potential, and—for neurons—cellular excitability ability to form synapses, release neurotransmitters and induce post-synaptic currents. Indeed, multiple studies demonstrate that DS cells have an impairment in all of the above-mentioned processes, and there is evidence that various interventions aimed at restoring mitochondrial activity can improve these functional parameters (Izzo et al 2017 ; Panagaki et al 2019 ; Park et al 2000 ; Jablonska et al 2006 ; Contestabile et al 2007 ; Trazzi et al 2011 ; Valenti et al 2013 ; Weick et al 2013 ; Bhattacharyya et al 2009 ; Stern et al 2015 ; Coskun et al 2017 ; Huo et al 2018 ; Mizuno et al 2018 ; Mollo et al 2019 ).…”

Section: Implications Conclusion and Outlookmentioning

confidence: 99%

Meta-analysis of metabolites involved in bioenergetic pathways reveals a pseudohypoxic state in Down syndrome

Pecze

Randi

Szabó

2020

Mol Med

View full text Add to dashboard Cite

Clinical observations and preclinical studies both suggest that Down syndrome (DS) may be associated with significant metabolic and bioenergetic alterations. However, the relevant scientific literature has not yet been systematically reviewed. The aim of the current study was to conduct a meta-analysis of metabolites involved in bioenergetics pathways in DS to conclusively determine the difference between DS and control subjects. We discuss these findings and their potential relevance in the context of pathogenesis and experimental therapy of DS. Articles published before July 1, 2020, were identified by using the search terms “Down syndrome” and “metabolite name” or “trisomy 21” and “metabolite name”. Moreover, DS-related metabolomics studies and bioenergetics literature were also reviewed. 41 published reports and associated databases were identified, from which the descriptive information and the relevant metabolomic parameters were extracted and analyzed. Mixed effect model revealed the following changes in DS: significantly decreased ATP, CoQ10, homocysteine, serine, arginine and tyrosine; slightly decreased ADP; significantly increased uric acid, succinate, lactate and cysteine; slightly increased phosphate, pyruvate and citrate. However, the concentrations of AMP, 2,3-diphosphoglycerate, glucose, and glutamine were comparable in the DS vs. control populations. We conclude that cells of subjects with DS are in a pseudo-hypoxic state: the cellular metabolic and bio-energetic mechanisms exhibit pathophysiological alterations that resemble the cellular responses associated with hypoxia, even though the supply of the cells with oxygen is not disrupted. This fundamental alteration may be, at least in part, responsible for a variety of functional deficits associated with DS, including reduced exercise difference, impaired neurocognitive status and neurodegeneration.

show abstract

Section: Implications Conclusion and Outlookmentioning

confidence: 99%

Meta-analysis of metabolites involved in bioenergetic pathways reveals a pseudohypoxic state in Down syndrome

Pecze

Randi

Szabó

2020

Mol Med

View full text Add to dashboard Cite

show abstract

“…Astrocytes support neuronal homoeostasis and regulate synaptic networks by promoting neuritogenesis and synaptogenesis 64 . However, DS astrocytes exert a toxic effect on the formation and maturation of neural networks and neuron survival by reducing neuronal activity, inducing morphological alterations, and promoting neuronal apoptosis 10,18,65 . In the DS brain, astrocytes may act as a primary effector in DS pathophysiology.…”

Section: Discussionmentioning

confidence: 99%

An isogenic cell line panel identifies major regulators of aberrant astrocyte proliferation in Down syndrome

Kawatani¹,

Nambara²,

Nawa³

et al. 2020

Preprint

View full text Add to dashboard Cite

Astrocytes exert adverse effects on the brains of individuals with Down syndrome (DS). Although a neurogenic-to-gliogenic shift in the fate-specification step has been reported, the mechanisms and key regulators underlying the accelerated proliferation of astrocyte precursor cells (APCs) in DS remain elusive. Here, we established an isogenic cell line panel, based on DS-specific induced pluripotent stem cells, the XIST-mediated transcriptional silencing system in trisomic chromosome 21, and genome/chromosome-editing technologies to eliminate phenotypic fluctuations caused by genetic variation. The transcriptional responses of genes observed upon XIST induction and/or downregulation were not uniform, and only a small subset of genes showed a characteristic expression pattern, which is consistent with the proliferative phenotypes of DS APCs. Comparative analysis and experimental verification using gene modification revealed dose-dependent proliferation-promoting activity of DYRK1A and PIGP on DS APCs. Our collection of isogenic cell lines provides a comprehensive set of cellular models for DS investigations.

show abstract

“…A central property in this context is Ca 2+ -dependent astroglial glutamate release, driving NMDA receptor-induced neuronal excitation and favoring neuronal synchrony (Parri et al, 2001;Angulo et al, 2004;Fellin et al, 2004;Tian et al, 2005;Poskanzer and Yuste, 2011;Sasaki et al, 2014). Importantly, astroglial Ca 2+ signals themselves are generally perturbed under neuropathological conditions (Kuchibhotla et al, 2009;Jiang et al, 2016;Mizuno et al, 2018;Shigetomi et al, 2019). Tonic long-lasting Ca 2+ elevations result at least partially from excitotoxic spilling of glutamate, GABA and ATP from dying cells (Shigetomi et al, 2019).…”

Section: Aberrant Ca 2+ Signaling and Network Excitability Disruptionmentioning

confidence: 99%

The Paradox of Astroglial Ca2 + Signals at the Interface of Excitation and Inhibition

Caudal

Gobbo

Scheller

et al. 2020

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Astroglial networks constitute a non-neuronal communication system in the brain and are acknowledged modulators of synaptic plasticity. A sophisticated set of transmitter receptors in combination with distinct secretion mechanisms enables astrocytes to sense and modulate synaptic transmission. This integrative function evolved around intracellular Ca2+ signals, by and large considered as the main indicator of astrocyte activity. Regular brain physiology meticulously relies on the constant reciprocity of excitation and inhibition (E/I). Astrocytes are metabolically, physically, and functionally associated to the E/I convergence. Metabolically, astrocytes provide glutamine, the precursor of both major neurotransmitters governing E/I in the central nervous system (CNS): glutamate and γ-aminobutyric acid (GABA). Perisynaptic astroglial processes are structurally and functionally associated with the respective circuits throughout the CNS. Astonishingly, in astrocytes, glutamatergic as well as GABAergic inputs elicit similar rises in intracellular Ca2+ that in turn can trigger the release of glutamate and GABA as well. Paradoxically, as gliotransmitters, these two molecules can thus strengthen, weaken or even reverse the input signal. Therefore, the net impact on neuronal network function is often convoluted and cannot be simply predicted by the nature of the stimulus itself. In this review, we highlight the ambiguity of astrocytes on discriminating and affecting synaptic activity in physiological and pathological state. Indeed, aberrant astroglial Ca2+ signaling is a key aspect of pathological conditions exhibiting compromised network excitability, such as epilepsy. Here, we gather recent evidence on the complexity of astroglial Ca2+ signals in health and disease, challenging the traditional, neuro-centric concept of segregating E/I, in favor of a non-binary, mutually dependent perspective on glutamatergic and GABAergic transmission.

show abstract

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

Cited by 44 publications

References 55 publications

Meta-analysis of metabolites involved in bioenergetic pathways reveals a pseudohypoxic state in Down syndrome

Meta-analysis of metabolites involved in bioenergetic pathways reveals a pseudohypoxic state in Down syndrome

An isogenic cell line panel identifies major regulators of aberrant astrocyte proliferation in Down syndrome

The Paradox of Astroglial Ca2 + Signals at the Interface of Excitation and Inhibition

Contact Info

Product

Resources

About