Role of Astrocytes in Delayed Neuronal Death: GLT-1 and its Novel Regulation by MicroRNAs

Ouyang, Yi‐Bing; Xu, Lijun; Liu, Siwei; Giffard, Rona G.

doi:10.1007/978-3-319-08894-5_9

Cited by 33 publications

(23 citation statements)

References 101 publications

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“…; for review, see Ouyang et al . ). Disruption of the BBB reduces GLT‐1 expression, reduces glutamate uptake, and results in spontaneous epileptic seizures in vivo (David et al .…”

Section: Discussionmentioning

confidence: 97%

Brain endothelial cells induce astrocytic expression of the glutamate transporter GLT‐1 by a Notch‐dependent mechanism

Lee

Martínez-Lozada

Krizman

et al. 2017

Journal of Neurochemistry

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Neuron-secreted factors induce astrocytic expression of the glutamate transporter, GLT-1 (EAAT2). In addition to their elaborate anatomic relationships with neurons, astrocytes also have processes that extend to and envelop the vasculature. Although previous studies have demonstrated that brain endothelia contribute to astrocyte differentiation and maturation, the effects of brain endothelia on astrocytic expression of GLT-1 have not been examined. In the present study, we tested the hypothesis that endothelia induce expression of GLT-1 by co-culturing astrocytes from mice that utilize non-coding elements of the GLT-1 gene to control expression reporter proteins with the mouse endothelial cell line, bEND.3. We found that endothelia increased steady state levels of reporter and GLT-1 mRNA/protein. Co-culturing with primary rat brain endothelia also increases reporter protein, GLT-1 protein, and GLT-1-mediated glutamate uptake. The Janus kinase/signal transducer and activator of transcription 3, bone morphogenic protein/transforming growth factor β, and nitric oxide pathways have been implicated in endothelia-to-astrocyte signaling; we provide multiple lines of evidence that none of these pathways mediate the effects of endothelia on astrocytic GLT-1 expression. Using transwells with a semi-permeable membrane, we demonstrate that the effects of the bEND.3 cell line are dependent upon contact. Notch has also been implicated in endothelia-astrocyte signaling in vitro and in vivo. The first step of Notch signaling requires cleavage of Notch intracellular domain (NICD) by γ-secretase. We demonstrate that the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) blocks endothelia-induced increases in GLT-1. We show that the levels of NICD are higher in nuclei of astrocytes co-cultured with endothelia, an effect also blocked by DAPT. Finally, infection of co-cultures with shRNA directed against recombination signal binding protein for immunoglobulin kappa J (RBPJ), a Notch effector, also reduces endothelia-dependent increases in eGFP and GLT-1. Together, these studies support a novel role for Notch in endothelia-dependent induction of GLT-1 expression.

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“…; for review, see Ouyang et al . ). Disruption of the BBB reduces GLT‐1 expression, reduces glutamate uptake, and results in spontaneous epileptic seizures in vivo (David et al .…”

Section: Discussionmentioning

confidence: 97%

Brain endothelial cells induce astrocytic expression of the glutamate transporter GLT‐1 by a Notch‐dependent mechanism

Lee

Martínez-Lozada

Krizman

et al. 2017

Journal of Neurochemistry

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“…Pyramidal neurons in the cornu ammonis 1 (CA1) region of the hippocampus are selectively sensitive to ischemia, dying in the days following reperfusion. However neurons in the adjacent dentate gyrus (DG) have a relatively higher ischemic resistance and survive (for review, Ouyang et al , 2014). Delayed neuronal death in the CA1 occurs secondary to disruption in mitochondrial function (Owens et al , 2015), inducing release of cytochrome c and other pro-apoptotic factors into the cytoplasm (Ouyang et al , 1999; Niizuma et al , 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Astrocytes, the most abundant cell type in the brain, play many key roles supporting normal neuronal functioning, including preserving ionic and acid-base balance, modulating neurotransmission, and maintaining neuronal energy stores (Clarke & Barres, 2013; Barreto et al , 2011). Critically, astrocyte homeostasis is tightly coupled to neuronal cell fate following ischemic injury (Nedergaard & Dirnagl, 2005; Barreto et al , 2011; Ouyang et al , 2014). We have previously observed that both neurons and astrocytes isolated from different brain regions show differential sensitivity to injuries (Xu et al , 2001).…”

Section: Introductionmentioning

confidence: 99%

miR-29a differentially regulates cell survival in astrocytes from cornu ammonis 1 and dentate gyrus by targeting VDAC1

et al. 2016

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Neurons in the cornu ammonis 1 (CA1) region of the hippocampus are vulnerable to cerebral ischemia, while dentate gyrus (DG) neurons are more resistant. This effect is mediated by local astrocytes, and may reflect differences in subregional hippocampal expression of miR-29a. We investigated the role of miR-29a on survival of hippocampal astrocytes cultured selectively from CA1 and DG in response to glucose deprivation (GD). CA1 astrocytes exhibited more cell death and a greater decrease in miR-29a than DG astrocytes. A reciprocal change was observed in the mitochondrial voltage dependent cation channel-1 (VDAC1), a regulator of mitochondria and target of miR-29a. In CA1 astrocytes, increasing miR-29a decreased VDAC1 and improved cell survival, while knockdown of VDAC1 improved survival. Finally, the protective effect of miR-29a was eliminated by inhibition of miR-29a/VDAC1 binding. These findings suggest that the selective vulnerability of the CA1 to injury may be due in part to a limited miR-29a response in CA1 astrocytes, allowing a greater increase in VDAC1-mediated cellular dysfunction in CA1 astrocytes.

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“…GLT-1 is so named due to its main distribution on glial cells. GLT-1 can remove excess glutamate and reduce excitotoxicity (7). Over 90% of glutamate uptake is carried out by GLT-1 in the adult forebrain (6).…”

Section: Introductionmentioning

confidence: 99%

Propofol protects hippocampal neurons from apoptosis in ischemic brain injury by increasing GLT-1 expression and inhibiting the activation of NMDAR via the JNK/Akt signaling pathway

Gong

Fang

Zhang

et al. 2016

International Journal of Molecular Medicine

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Ischemic brain injury (IBI) can cause nerve injury and is a leading cause of morbidity and mortality worldwide. The neuroprotective effects of propofol against IBI have been previously demonstrated. However, the neuroprotective effects of propofol on hippocampal neurons are not yet entirely clear. In the present study, models of IBI were established in hypoxia-exposed hippocampal neuronal cells. Cell viability assay and apoptosis assay were performed to examine the neuroprotective effects of propofol on hippocampal neurons in IBI. A significant decrease in cell viability and a significant increase in cell apoptosis were observed in the IBI group compared with the control group, accompanied by a decrease in glial glutamate transporter-1 (GLT‑1) expression as determined by RT-qPCR and western blot analysis. The effects of IBI were reversed by propofol treatment. The siRNA-mediated knockdown of GLT‑1 in the hypoxia-exposed hippocampal neuronal cells led to an increase in cell apoptosis, Jun N-terminal kinase (JNK) activation and N-methyl-D‑aspartate (NMDA) receptor (NR1 and NR2B) activation, as well as to a decrease in cell viability and a decrease in Akt activation. The effects of RNA interference-mediated GLT‑1 gene silencing on cell viability, JNK activation, NMDAR activation, cell apoptosis and Akt activation in the hippocampal neuronal cells were slightly reversed by propofol treatment. The JNK agonist, anisomycin, and the Akt inhibitor, LY294002, both significantly blocked the effects of propofol on hippocampal neuronal cell viability and apoptosis in IBI. The decrease in JNK activation and the increase in Akt activation caused by GLT‑1 overexpression were reversed by NMDA. Collectively, our findings suggest that propofol treatment protects hippocampal neurons against IBI by enhancing GLT‑1 expression and inhibiting the activation of NMDAR via the JNK/Akt signaling pathway.

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Role of Astrocytes in Delayed Neuronal Death: GLT-1 and its Novel Regulation by MicroRNAs

Cited by 33 publications

References 101 publications

Brain endothelial cells induce astrocytic expression of the glutamate transporter GLT‐1 by a Notch‐dependent mechanism

Brain endothelial cells induce astrocytic expression of the glutamate transporter GLT‐1 by a Notch‐dependent mechanism

miR-29a differentially regulates cell survival in astrocytes from cornu ammonis 1 and dentate gyrus by targeting VDAC1

Propofol protects hippocampal neurons from apoptosis in ischemic brain injury by increasing GLT-1 expression and inhibiting the activation of NMDAR via the JNK/Akt signaling pathway

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