scholarly journals Astrocytes Maintain Glutamate Homeostasis in the CNS by Controlling the Balance between Glutamate Uptake and Release

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 184 ◽  
Author(s):  
Shaimaa Mahmoud ◽  
Marjan Gharagozloo ◽  
Camille Simard ◽  
Denis Gris
Keyword(s):  
Molecular Mechanisms ◽  
Glutamate Uptake ◽  
Glutamate Release ◽  
Neuronal Firing ◽  
Glutamate Excitotoxicity ◽  
Dual Function ◽  
Cns Diseases ◽  
Glutamate Homeostasis ◽  
Neuronal Functions ◽  
Uptake And Release

Glutamate is one of the most prevalent neurotransmitters released by excitatory neurons in the central nervous system (CNS); however, residual glutamate in the extracellular space is, potentially, neurotoxic. It is now well-established that one of the fundamental functions of astrocytes is to uptake most of the synaptically-released glutamate, which optimizes neuronal functions and prevents glutamate excitotoxicity. In the CNS, glutamate clearance is mediated by glutamate uptake transporters expressed, principally, by astrocytes. Interestingly, recent studies demonstrate that extracellular glutamate stimulates Ca2+ release from the astrocytes’ intracellular stores, which triggers glutamate release from astrocytes to the adjacent neurons, mostly by an exocytotic mechanism. This released glutamate is believed to coordinate neuronal firing and mediate their excitatory or inhibitory activity. Therefore, astrocytes contribute to glutamate homeostasis in the CNS, by maintaining the balance between their opposing functions of glutamate uptake and release. This dual function of astrocytes represents a potential therapeutic target for CNS diseases associated with glutamate excitotoxicity. In this regard, we summarize the molecular mechanisms of glutamate uptake and release, their regulation, and the significance of both processes in the CNS. Also, we review the main features of glutamate metabolism and glutamate excitotoxicity and its implication in CNS diseases.

scholarly journals NLRX1 Enhances Glutamate Uptake and Inhibits Glutamate Release by Astrocytes

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 400 ◽  
Author(s):  
Shaimaa Mahmoud ◽  
Marjan Gharagozloo ◽  
Camille Simard ◽  
Abdelaziz Amrani ◽  
Denis Gris
Keyword(s):  
Glutamate Uptake ◽  
Glutamate Release ◽  
Neuronal Firing ◽  
Glutamate Excitotoxicity ◽  
Cns Inflammation ◽  
Atp Production ◽  
Inflammatory Conditions ◽  
Mitochondrial Functions ◽  
The Central Nervous System ◽  
First Time

Uptake of glutamate from the extracellular space and glutamate release to neurons are two major processes conducted by astrocytes in the central nervous system (CNS) that protect against glutamate excitotoxicity and strengthen neuronal firing, respectively. During inflammatory conditions in the CNS, astrocytes may lose one or both of these functions, resulting in accumulation of the extracellular glutamate, which eventually leads to excitotoxic neuronal death, which in turn worsens the CNS inflammation. NLRX1 is an innate immune NOD-like receptor that inhibits the major inflammatory pathways. It is localized in the mitochondria and was shown to inhibit cell death, enhance ATP production, and dampen oxidative stress. In the current work, using primary murine astrocyte cultures from WT and Nlrx1-/- mice, we demonstrate that NLRX1 potentiates astrocytic glutamate uptake by enhancing mitochondrial functions and the functional activity of glutamate transporters. Also, we report that NLRX1 inhibits glutamate release from astrocytes by repressing Ca2+-mediated glutamate exocytosis. Our study, for the first time, identified NLRX1 as a potential regulator of glutamate homeostasis in the CNS.

Platelet Glutamate Uptake and Release in Migraine With and Without Aura

Cephalalgia ◽  
2007 ◽  
Vol 27 (1) ◽  
pp. 35-40 ◽  
Author(s):  
M Vaccaro ◽  
C Riva ◽  
L Tremolizzo ◽  
M Longoni ◽  
A Aliprandi ◽  
...  
Keyword(s):  
Amino Acid ◽  
High Performance ◽  
Spreading Depression ◽  
Glutamate Uptake ◽  
Glutamate Release ◽  
Plasma Concentrations ◽  
Control Group ◽  
Therapeutic Approaches ◽  
The Brain ◽  
Uptake And Release

Glutamate may play an important role in the pathogenesis of migraine: glutamate release in the brain may be involved in the development of spreading depression and increased concentrations of this amino acid have been reported in plasma and platelets from migraine patients. Here we assessed platelet glutamate uptake and release in 25 patients affected by migraine with aura (MA) and 25 patients affected by migraine without aura (MoA), comparing the results with a group of 20 healthy matched controls. Both glutamate release from stimulated platelets and plasma concentrations of the amino acid were assessed by high-performance liquid chromatography, and were increased in both types of migraine, although more markedly in MA. Platelet glutamate uptake, assessed as 3H-glutamate intake, was increased in MA, while it was reduced in MoA with respect to the control group. These results support the view that MA might involve different pathophysiological mechanisms from MoA and, specifically, up-regulation of the glutamatergic metabolism. Understanding these dysfunctional pathways could lead to new, possibly more successful therapeutic approaches to the management of migraine.

Interaction between glutamate signalling and immune attack in damaging oligodendrocytes

2007 ◽  
Vol 3 (4) ◽  
pp. 281-285 ◽  
Author(s):  
Carlos Matute
Keyword(s):  
Glutamate Receptors ◽  
Glutamate Uptake ◽  
Kainate Receptors ◽  
Glutamate Excitotoxicity ◽  
Excitatory Neurotransmitter ◽  
Glutamate Signaling ◽  
Immune Attack ◽  
Glutamate Homeostasis

AbstractGlutamate is the principal excitatory neurotransmitter in the CNS, but it is also a potent neurotoxin that can kill nerve cells. Glutamate damages oligodendrocytes, like neurons, by excitotoxicity which is caused by sustained activation of AMPA, kainate and NMDA receptors. Glutamate excitotoxicity depends entirely on Ca2+ overload of the cytoplasm and can be initiated by disruption of glutamate homeostasis. Thus, inhibition of glutamate uptake in isolated oligodendrocytes in vitro and in the optic nerve in vivo, is sufficient to trigger cell death which is prevented by glutamate receptor antagonists. In turn, activated, but not resting microglia, can compromise glutamate homeostasis and induce oligodendrocyte excitotoxicity, which is attenuated either by AMPA/kainate antagonists or by the blockade of the system xc_ antiporter present in microglia. By contrast, non-lethal, brief, activation of glutamate receptors in oligodendrocytes rapidly sensitizes these cells to complement attack. Intriguingly, these effects are exclusively mediated by kainate receptors which induce Ca2+ overload of the cytosol and the generation of reactive oxygen species. In conjunction, these observations reveal novel mechanisms by which neuroinflammation alters glutamate homeostasis and triggers oligodendrocyte death. Conversely, they also show how glutamate signaling in oligodendrocytes might induce immune attack. In both instances direct activation of glutamate receptors present in oligodendrocytes plays a pivotal role in either initiating or executing death signals, which might be relevant to the pathogenesis of white matter disorders.

scholarly journals Enmein Decreases Synaptic Glutamate Release and Protects against Kainic Acid-Induced Brain Injury in Rats

2021 ◽  
Vol 22 (23) ◽  
pp. 12966
Author(s):  
Cheng-Wei Lu ◽  
Yu-Chen Huang ◽  
Kuan-Ming Chiu ◽  
Ming-Yi Lee ◽  
Tzu-Yu Lin ◽  
...  
Keyword(s):  
Kainic Acid ◽  
Rat Model ◽  
Cell Activation ◽  
Excitatory Amino Acid ◽  
Glutamate Uptake ◽  
Glutamate Release ◽  
Intraperitoneal Administration ◽  
Neuronal Cell ◽  
Glutamate Excitotoxicity ◽  
Nerve Terminals

This study investigated the effects of enmein, an active constituent of Isodon japonicus Hara, on glutamate release in rat cerebrocortical nerve terminals (synaptosomes) and evaluated its neuroprotective potential in a rat model of kainic acid (KA)-induced glutamate excitotoxicity. Enmein inhibited depolarization-induced glutamate release, FM1-43 release, and Ca2+ elevation in cortical nerve terminals but had no effect on the membrane potential. Removing extracellular Ca2+ and blocking vesicular glutamate transporters, N- and P/Q-type Ca2+ channels, or protein kinase C (PKC) prevented the inhibition of glutamate release by enmein. Enmein also decreased the phosphorylation of PKC, PKC-α, and myristoylated alanine-rich C kinase substrates in synaptosomes. In the KA rat model, intraperitoneal administration of enmein 30 min before intraperitoneal injection of KA reduced neuronal cell death, glial cell activation, and glutamate elevation in the hippocampus. Furthermore, in the hippocampi of KA rats, enmein increased the expression of synaptic markers (synaptophysin and postsynaptic density protein 95) and excitatory amino acid transporters 2 and 3, which are responsible for glutamate clearance, whereas enmein decreased the expression of glial fibrillary acidic protein (GFAP) and CD11b. These results indicate that enmein not only inhibited glutamate release from cortical synaptosomes by suppressing Ca2+ influx and PKC but also increased KA-induced hippocampal neuronal death by suppressing gliosis and decreasing glutamate levels by increasing glutamate uptake.

Regulation of Amino Acid Transport in Glioma

Neurosurgery ◽  
2019 ◽  
Vol 66 (Supplement_1) ◽  
Author(s):  
Stephanie Robert ◽  
Robyn Umans ◽  
Joelle Martin ◽  
Harald Sontheimer
Keyword(s):  
Tumor Growth ◽  
Glutamate Uptake ◽  
Glutamate Release ◽  
Brain Slices ◽  
Glutamate Excitotoxicity ◽  
Transcriptional Level ◽  
Pharmacological Inhibition ◽  
Electrophysiological Recordings ◽  
Elevated Expression

Abstract INTRODUCTION Glutamate is an important molecule in the biology of brain tumors. Glutamate reaches toxic concentrations in peritumoral tissue, contributing to tumor growth and peritumoral excitotoxicity. Mediated by the cystine-glutamate exchanger, System xc- (SXC), glutamate uptake allows production of the antioxidant glutathione (GSH), which protects cells from damage and cell death. We have shown SXC is variably expressed among glioma patients, with ∼50% demonstrating elevated expression, associated seizures, and glutamate excitotoxicity. In a clinical pilot study, we found pharmacological inhibition of SXC reduces glutamate release in gliomas with elevated SXC. We now hypothesize that differences in SXC expression is due to transcriptional and co-receptor regulation, specifically, by p53 and CD44. METHODS This study utilizes in Vivo propagated glioma xenolines to test the consequences of p53 and CD44 loss on SXC function. We use siRNA/shRNA against p53/CD44, and glutamate assays to test SXC function, as well as chromatin immunopreciptiation (ChIP) assay and immunofluorescence to detail the relationship between between p53/CD44 and SXC. Lastly, using electrophysiological recordings in live brain slices, we test peritumoral excitotoxicity due to SXC function in setting of p54/CD44 loss to determine glutamate excitotoxicity on the surrounding brain. RESULTS SXC activity and glutamate release is altered by p53 and CD44 expression, altering peritumoral excitotoxicity, invasion, and tumor growth. P53 activity transcriptionally suppresses SXC and prevents glutamate release. Furthermore, SXC is also regulated by the hyaluronan receptor CD44. CD44 appears to be a membrane co-receptor of SXC, and loss of CD44 results in decreased SXC function, and consequently the ability of glioma cells to invade and grow. CONCLUSION These studies explore new strategies to alter the abnormal glutamate biology of gliomas at a transcriptional level, which is advantageous given poor options for pharmacological inhibition of SXC. Furthermore, the expression of p53 and CD44 may have predictive value regarding treatment and prognosis of glioma.

scholarly journals Ketamine Alters Functional Plasticity of Astroglia: An Implication for Antidepressant Effect

Life ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 573
Author(s):  
Matjaž Stenovec
Keyword(s):  
Molecular Mechanisms ◽  
Neuronal Firing ◽  
Fusion Pore ◽  
Antidepressant Effect ◽  
Intracellular Camp ◽  
Lateral Habenula ◽  
Vesicle Recycling ◽  
The Central Nervous System ◽  
Inward Rectifying Potassium Channel ◽  
Antidepressant Action

Ketamine, a non-competitive N–methyl–d–aspartate receptor (NMDAR) antagonist, exerts a rapid, potent and long-lasting antidepressant effect, although the cellular and molecular mechanisms of this action are yet to be clarified. In addition to targeting neuronal NMDARs fundamental for synaptic transmission, ketamine also affects the function of astrocytes, the key homeostatic cells of the central nervous system that contribute to pathophysiology of major depressive disorder. Here, I review studies revealing that (sub)anesthetic doses of ketamine elevate intracellular cAMP concentration ([cAMP]i) in astrocytes, attenuate stimulus-evoked astrocyte calcium signaling, which regulates exocytotic secretion of gliosignaling molecules, and stabilize the vesicle fusion pore in a narrow configuration, possibly hindering cargo discharge or vesicle recycling. Next, I discuss how ketamine affects astrocyte capacity to control extracellular K+ by reducing vesicular delivery of the inward rectifying potassium channel (Kir4.1) to the plasmalemma that reduces the surface density of Kir4.1. Modified astroglial K+ buffering impacts upon neuronal firing pattern as demonstrated in lateral habenula in a rat model of depression. Finally, I highlight the discovery that ketamine rapidly redistributes cholesterol in the astrocyte plasmalemma, which may alter the flux of cholesterol to neurons. This structural modification may further modulate a host of processes that synergistically contribute to ketamine’s rapid antidepressant action.

scholarly journals Ischemic Preconditioning Reveals that GLT1/EAAT2 Glutamate Transporter is a Novel PPARγ Target Gene Involved in Neuroprotection

2007 ◽  
Vol 27 (7) ◽  
pp. 1327-1338 ◽  
Author(s):  
Cristina Romera ◽  
Olivia Hurtado ◽  
Judith Mallolas ◽  
Marta P Pereira ◽  
Jesús R Morales ◽  
...  
Keyword(s):  
Nervous System ◽  
Ischemic Preconditioning ◽  
Transcriptional Activity ◽  
Target Gene ◽  
Glutamate Uptake ◽  
Glutamate Release ◽  
Glutamate Transporter ◽  
Glutamate Transport ◽  
Extracellular Glutamate ◽  
Pparγ Agonist

Excessive levels of extracellular glutamate in the nervous system are excitotoxic and lead to neuronal death. Glutamate transport, mainly by glutamate transporter GLT1/EAAT2, is the only mechanism for maintaining extracellular glutamate concentrations below excitotoxic levels in the central nervous system. We recently showed that neuroprotection after experimental ischemic preconditioning (IPC) involves, at least partly, the upregulation of the GLT1/EAAT2 glutamate transporter in astrocytes, but the mechanisms were unknown. Thus, we decided to explore whether activation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)γ, known for its antidiabetic and antiinflammatory properties, is involved in glutamate transport. First, we found that the PPARγ antagonist T0070907 inhibits both IPC-induced tolerance and reduction of glutamate release after lethal oxygen-glucose deprivation (OGD) (70.1% ± 3.4% versus 97.7% ± 5.2% of OGD-induced lactate dehydrogenase (LDH) release and 61.8% ± 5.9% versus 85.9% ± 7.9% of OGD-induced glutamate release in IPC and IPC + T0070907 1 μmol/L, respectively, n = 6 to 12, P < 0.05), as well as IPC-induced astrocytic GLT-1 overexpression. IPC also caused an increase in nuclear PPARγ transcriptional activity in neurons and astrocytes (122.1% ± 8.1% and 158.6% ± 22.6% of control PPARγ transcriptional activity, n = 6, P < 0.05). Second, the PPARγ agonist rosiglitazone increased both GLT-1/EAAT2 mRNA and protein expression and [3H]glutamate uptake, and reduced OGD-induced cell death and glutamate release (76.3% ± 7.9% and 65.5% ± 15.1% of OGD-induced LDH and glutamate release in rosiglitazone 1 μmol/l, respectively, n = 6 to 12, P < 0.05). Finally, we have identified six putative PPAR response elements (PPREs) in the GLT1/EAAT2 promoter and, consistently, rosiglitazone increased fourfold GLT1/EAAT2 promoter activity. All these data show that the GLT1/EAAT2 glutamate transporter is a target gene of PPARγ leading to neuroprotection by increasing glutamate uptake.

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