A Central Role for ATP Signalling in Glial Interactions in the CNS

Rivera, Andrea; Vanzulli, Ilaria; Butt, Arthur M.

doi:10.2174/1389450117666160711154529

Cited by 60 publications

(44 citation statements)

References 58 publications

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“…In the case of epilepsy, disruption of inhibitory transmission in GCs has also been shown to enhance excitability of these cells during the latent period (Pathak et al, ). Finally, our observation that specific activation of astrocytes by optogenetics mimics the effects of TNFα on the frequency of mEPSCs and also involves P2Y1 receptor activation and the presence of extracellular ATP further supports the idea that purinergic signaling in astrocytes, and not in other cell types (e.g., oligodendrocytes, see Rivera, Vanzulli, & Butt, ), is the key element mediating the effects of TNFα on excitatory synaptic activity in GCs.…”

Section: Discussionsupporting

confidence: 74%

Blocking TNFα‐driven astrocyte purinergic signaling restores normal synaptic activity during epileptogenesis

Nikolić

Shen

Nobili

et al. 2018

Glia

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Epilepsy is characterized by unpredictable recurrent seizures resulting from abnormal neuronal excitability. Increasing evidence indicates that aberrant astrocyte signaling to neurons plays an important role in driving the network hyperexcitability, but the underlying mechanism that alters glial signaling in epilepsy remains unknown. Increase in glutamate release by astrocytes participates in the onset and progression of seizures. Epileptic seizures are also accompanied by increase of tumor necrosis factor alpha (TNFα), a cytokine involved in the regulation of astrocyte glutamate release. Here we tested whether TNFα controls abnormal astrocyte glutamate signaling in epilepsy and through which mechanism. Combining Ca2+ imaging, optogenetics, and electrophysiology, we report that TNFα triggers a Ca2+‐dependent glutamate release from astrocytes that boosts excitatory synaptic activity in the hippocampus through a mechanism involving autocrine activation of P2Y1 receptors by astrocyte‐derived ATP/ADP. In a mouse model of temporal lobe epilepsy, such TNFα‐driven astrocytic purinergic signaling is permanently active, promotes glial glutamate release, and drives abnormal synaptic activity in the hippocampus. Blocking this pathway by inhibiting P2Y1 receptors restores normal excitatory synaptic activity in the inflamed hippocampus. Our findings indicate that targeting the coupling of TNFα with astrocyte purinergic signaling may be a therapeutic strategy for reducing glial glutamate release and normalizing synaptic activity in epilepsy.

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Section: Discussionsupporting

confidence: 74%

Blocking TNFα‐driven astrocyte purinergic signaling restores normal synaptic activity during epileptogenesis

Nikolić

Shen

Nobili

et al. 2018

Glia

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“…P2X7 is also expressed in central nervous system cells: microglia, astrocytes and oligodendrocytes, whereas its presence in neurons is still a subject of the debate (Illes et al, 2017;Miras-Portugal et al, 2017;Kaczmarek-Hajek et al, 2018). Importantly, glia and neurons use the extracellular ATP to communicate and to maintain the homeostasis in the brain; moreover, ATP may be also released from damaged CNS cells (Rivera et al, 2016). It is not surprising then, that ATP-gated P2X7 is involved in many physiological and pathological processes in CNS, such as neurotransmission (Sperlágh et al, 2002), phagocytosis during brain development (Gu & Wiley, 2018), immunological cells infiltration (Panenka et al, 2001) as well as neurodegenerative diseases, psychiatric disorders and neuroinflammation (Sperlágh & Illes, 2014 P2X7 receptor signaling is also believed to play a crucial role in gliomas which represent most of the CNS malignant tumors and are characterized with very poor prognosis (Jiang & Uhrbom, 2012).…”

Section: Introductionmentioning

confidence: 99%

P2X7 receptor activity landscape in rat and human glioma cell lines

2020

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P2X7 is a commonly expressed purinergic receptor, which functions as a cation-permeable channel in the plasma membrane. In certain circumstances, the receptor may also form a large transmembrane pore what results in cell death. P2X7 receptors control numerous physiological and pathological cellular processes and their overexpression is often associated with cancer progression. As nucleotides are important signaling molecules in the central nervous system, P2X7 plays also an important but ambiguous role in glioma biology with contrary observations originating from different glioma models. Therefore, the aim of our research was to investigate P2X7 receptor expression and functions in three human (U-87 MG, U-138 MG, U-251 MG) and one rat (C6) glioma cell lines. Although the receptor mRNA and protein were present in all the studied cells, we found profound differences in their level. We also encountered a problem with one human cell lines authenticity (U-87 MG) and excluded it from most of the experiments. Interestingly, there was no clear dependency between P2X7 receptor level, calcium signal and pore formation ability in the studied glioma lines. In U-138 human cell line, the receptor seemed to be inactive, while in U-251 human and C6 rat cell line its activation resulted in calcium influx and large pore formation. However, the viability of studied cells upon the administration of specific P2X7 agonist -BzATP -was not affected for U-138 and U-251, whereas for C6 cells a stimulatory effect was observed. Our results stress the variability of P2X7 signaling in glioma models and the need for future research which would take into account the complicated landscape of the receptor signaling in the brain.

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“…VDAC1 downregulation has been reported to reduce cellular ATP levels and induce mitochondrial fragmentation (45,46), eventually leading to by guest, on May 11, 2018 www.jlr.org Downloaded from neurodegeneration. In astrocytes, VDAC1 is critical for secretion of ATP, a gliotransmitter regulating synaptic plasticity and neuronal function (47)(48)(49)(50). Most recently, VDAC1 closure by tubulin has been suggested to be critical for the Warburg effect, a metabolic switch from mitochondria-mediated oxidative phosphorylation to glycolysis for ATP production, often observed in cancer cells (51)(52)(53).…”

Section: Introductionmentioning

confidence: 99%