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10 publication(s) since Octobre 2008:

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03/03/2020 | Cell Metab   IF 21.6
Impairment of Glycolysis-Derived l-Serine Production in Astrocytes Contributes to Cognitive Deficits in Alzheimer's Disease.
Le Douce J, Maugard M, Veran J, Matos M, Jego P, Vigneron PA, Faivre E, Toussay X, Vandenberghe M, Balbastre Y, Piquet J, Guiot E, Tran NT, Taverna M, Marinesco S, Koyanagi A, Furuya S, Gaudin-Guerif M, Goutal S, Ghettas A, Pruvost A, Bemelmans AP, Gaillard MC, Cambon K, Stimmer L, Sazdovitch V, Duyckaerts C, Knott G, Herard AS, Delzescaux T, Hantraye P, Brouillet E, Cauli B, Oliet SHR, Panatier A, Bonvento G

Alteration of brain aerobic glycolysis is often observed early in the course of Alzheimer's disease (AD). Whether and how such metabolic dysregulation contributes to both synaptic plasticity and behavioral deficits in AD is not known. Here, we show that the astrocytic l-serine biosynthesis pathway, which branches from glycolysis, is impaired in young AD mice and in AD patients. l-serine is the precursor of d-serine, a co-agonist of synaptic NMDA receptors (NMDARs) required for synaptic plasticity. Accordingly, AD mice display a lower occupancy of the NMDAR co-agonist site as well as synaptic and behavioral deficits. Similar deficits are observed following inactivation of the l-serine synthetic pathway in hippocampal astrocytes, supporting the key role of astrocytic l-serine. Supplementation with l-serine in the diet prevents both synaptic and behavioral deficits in AD mice. Our findings reveal that astrocytic glycolysis controls cognitive functions and suggest oral l-serine as a ready-to-use therapy for AD.

16/10/2018 | Acta Neuropathol Commun   IF 6.3
Modulation of astrocyte reactivity improves functional deficits in mouse models of Alzheimer's disease.
Ceyzeriat K, Ben Haim L, Denizot A, Pommier D, Matos M, Guillemaud O, Palomares MA, Abjean L, Petit F, Gipchtein P, Gaillard MC, Guillermier M, Bernier S, Gaudin M, Auregan G, Josephine C, Dechamps N, Veran J, Langlais V, Cambon K, Bemelmans AP, Baijer J, Bonvento G, Dhenain M, Deleuze JF, Oliet SHR, Brouillet E, Hantraye P, Carrillo-de Sauvage MA, Olaso R, Panatier A, Escartin C

Astrocyte reactivity and neuroinflammation are hallmarks of CNS pathological conditions such as Alzheimer's disease. However, the specific role of reactive astrocytes is still debated. This controversy may stem from the fact that most strategies used to modulate astrocyte reactivity and explore its contribution to disease outcomes have only limited specificity. Moreover, reactive astrocytes are now emerging as heterogeneous cells and all types of astrocyte reactivity may not be controlled efficiently by such strategies.Here, we used cell type-specific approaches in vivo and identified the JAK2-STAT3 pathway, as necessary and sufficient for the induction and maintenance of astrocyte reactivity. Modulation of this cascade by viral gene transfer in mouse astrocytes efficiently controlled several morphological and molecular features of reactivity. Inhibition of this pathway in mouse models of Alzheimer's disease improved three key pathological hallmarks by reducing amyloid deposition, improving spatial learning and restoring synaptic deficits.In conclusion, the JAK2-STAT3 cascade operates as a master regulator of astrocyte reactivity in vivo. Its inhibition offers new therapeutic opportunities for Alzheimer's disease.

12/10/2018 | Nat Commun   IF 12.1
Astrocytes detect and upregulate transmission at inhibitory synapses of somatostatin interneurons onto pyramidal cells.
Matos M, Bosson A, Riebe I, Reynell C, Vallee J, Laplante I, Panatier A, Robitaille R, Lacaille JC

Astrocytes are important regulators of excitatory synaptic networks. However, astrocytes regulation of inhibitory synaptic systems remains ill defined. This is particularly relevant since GABAergic interneurons regulate the activity of excitatory cells and shape network function. To address this issue, we combined optogenetics and pharmacological approaches, two-photon confocal imaging and whole-cell recordings to specifically activate hippocampal somatostatin or paravalbumin-expressing interneurons (SOM-INs or PV-INs), while monitoring inhibitory synaptic currents in pyramidal cells and Ca(2+) responses in astrocytes. We found that astrocytes detect SOM-IN synaptic activity via GABABR and GAT-3-dependent Ca(2+) signaling mechanisms, the latter triggering the release of ATP. In turn, ATP is converted into adenosine, activating A1Rs and upregulating SOM-IN synaptic inhibition of pyramidal cells, but not PV-IN inhibition. Our findings uncover functional interactions between a specific subpopulation of interneurons, astrocytes and pyramidal cells, involved in positive feedback autoregulation of dendritic inhibition of pyramidal cells.

2016 | j neuroinflammation   IF 5.8
Oncostatin M promotes excitotoxicity by inhibiting glutamate uptake in astrocytes: implications in HIV-associated neurotoxicity.
Moidunny S, Matos M, Wesseling E, Banerjee S, Volsky DJ, Cunha RA, Agostinho P, Boddeke HW, Roy S

BACKGROUND: Elevated levels of oncostatin M (OSM), an interleukin-6 cytokine family member, have been observed in HIV-1-associated neurocognitive disorders (HAND) and Alzheimer's disease. However, the function of OSM in these disease conditions is unclear. Since deficient glutamate uptake by astrocytes is instrumental in HAND-associated neurotoxicity, we hypothesized that OSM impairs glutamate uptake in astrocytes and thereby promotes neuronal excitotoxicity. METHODS: Primary cultures of mouse cortical astrocytes, neurons, microglia, and BV2 cell line were used. The expression of glutamate transporters (GLAST/EAAT1 and GLT-1/EAAT2) was investigated using real-time PCR and Western blot, and their activity was assessed by measuring (3)H-D-aspartate uptake. Neuronal toxicity was measured using the colorimetric MTT (3-(4,5-dimethylthiazol-2-yl-) 2,5-diphenyltetrazolium bromide) assay and immunocytochemistry. A chimeric HIV-1 that infects murine cells (EcoHIV/NL4-3-GFP virus (EcoHIV)) was used to investigate whether the virus induces OSM, OSM receptor (OSMR)-beta, glycoprotein 130 (gp130), GLT-1, GLAST (mRNA and protein), and OSM release (ELISA) in cultured BV2 cells, primary microglia, or astrocytes. Statistical analyses of the data were performed using one-way ANOVA (to allow multiple comparisons) and two-tailed Student's t test. RESULTS: OSM treatment (10 ng/mL) time-dependently reduced GLAST and GLT-1 expression and inhibited (3)H-D-aspartate uptake in cultured astrocytes in a concentration-dependent manner, an effect prevented by the Janus kinase (JAK)/signal transducers and activators of transcription (STAT)3 inhibitor AG490. Down-regulation of astrocytic glutamate transport by OSM resulted in NMDA receptor-dependent excitotoxicity in cortical neurons. Infection with EcoHIV induced OSM gene expression and protein release in BV2 cells and microglia, but not in astrocytes. Conversely, EcoHIV caused a fivefold increase in OSMR-beta mRNA (but not gp130) and protein in astrocytes, but not in microglia, which did not express OSMR-beta protein. Finally, astrocytic expression of GLAST gene was unaffected by EcoHIV, whereas GLT-1 mRNA was increased by twofold. CONCLUSIONS: We provide first evidence that activation of JAK/STAT3 signaling by OSM inhibits glutamate uptake in astrocytes, which results in neuronal excitotoxicity. Our findings with EcoHIV suggest that targeting OSMR-beta signaling in astrocytes might alleviate HIV-1-associated excitotoxicity.

01/12/2015 | Biol Psychiatry   IF 12.1
Deletion of adenosine A2A receptors from astrocytes disrupts glutamate homeostasis leading to psychomotor and cognitive impairment: relevance to schizophrenia.
Matos M, Shen HY, Augusto E, Wang Y, Wei CJ, Wang YT, Agostinho P, Boison D, Cunha RA, Chen JF

BACKGROUND: Adenosine A2A receptors (A2AR) modulate dopamine and glutamate signaling and thereby may influence some of the psychomotor and cognitive processes associated with schizophrenia. Because astroglial A2AR regulate the availability of glutamate, we hypothesized that they might play an unprecedented role in some of the processes leading to the development of schizophrenia, which we investigated using a mouse line with a selective deletion of A2AR in astrocytes (Gfa2-A2AR knockout [KO] mice]. METHODS: We examined Gfa2-A2AR KO mice for behaviors thought to recapitulate some features of schizophrenia, namely enhanced MK-801 psychomotor response (positive symptoms) and decreased working memory (cognitive symptoms). In addition, we probed for neurochemical alterations in the glutamatergic circuitry, evaluating glutamate uptake and release and the levels of key proteins defining glutamatergic signaling (glutamate transporter-I [GLT-I], N-methyl-D-aspartate receptors [NMDA-R] and alpha-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors [AMPA-R]) to provide a mechanistic understanding of the phenotype encountered. RESULTS: We show that Gfa2-A2AR KO mice exhibited enhanced MK-801 psychomotor response and decreased working memory; this was accompanied by a disruption of glutamate homeostasis characterized by aberrant GLT-I activity, increased presynaptic glutamate release, NMDA-R 2B subunit upregulation, and increased internalization of AMPA-R. Accordingly, selective GLT-I inhibition or blockade of GluR1/2 endocytosis prevented the psychomotor and cognitive phenotypes in Gfa2-A2AR KO mice, namely in the nucleus accumbens. CONCLUSIONS: These results show that the dysfunction of astrocytic A2AR, by controlling GLT-I activity, triggers an astrocyte-to-neuron wave of communication resulting in disrupted glutamate homeostasis, thought to underlie several endophenotypes relevant to schizophrenia.

20/11/2013 | J Neurosci   IF 5.7
Antagonistic interaction between adenosine A2A receptors and Na+/K+-ATPase-alpha2 controlling glutamate uptake in astrocytes.
Matos M, Augusto E, Agostinho P, Cunha RA, Chen JF

Astrocytic glutamate transporter-1 (GLT-I) is critical to control the bulk of glutamate uptake and, thus, to regulate synaptic plasticity and excitotoxicity. GLT-I glutamate uptake is driven by the sodium gradient implemented by Na(+)/K(+)-ATPases (NKAs) and the alpha2 subunit of NKA (NKA-alpha2) is actually linked to GLT-I to regulate astrocytic glutamate transport. We recently found that adenosine A2A receptors (A2ARs), which control synaptic plasticity and neurodegeneration, regulate glutamate uptake through unknown mechanisms. Here we report that A2AR activation decreases NKA activity selectively in astrocytes to inhibit glutamate uptake. Furthermore, we found a physical association of A2ARs with NKA-alpha2s in astrocytes, as gauged by coimmunoprecipitation and in situ proximity ligation assays, in the cerebral cortex and striatum, two brain regions where A2ARs inhibit the astrocytic glutamate uptake. Moreover, the selective deletion of A2ARs in astrocytes (using Gfa2-A2AR-KO mice) leads to a concurrent increase of both astrocytic glutamate uptake and NKA-alpha2 levels and activity in the striatum and cortex. This coupling of astrocytic A2ARs to the regulation of glutamate transport through modulation of NKA-alpha2 activity provides a novel mechanism linking neuronal activity to ion homeostasis controlling glutamatergic activity, all of which are processes intricately associated with the etiology of several brain diseases.

10/07/2013 | J Neurosci   IF 5.7
Ecto-5'-nucleotidase (CD73)-mediated formation of adenosine is critical for the striatal adenosine A2A receptor functions.
Augusto E, Matos M, Sevigny J, El-Tayeb A, Bynoe MS, Muller CE, Cunha RA, Chen JF

Adenosine is a neuromodulator acting through inhibitory A1 receptors (A1Rs) and facilitatory A2ARs, which have similar affinities for adenosine. It has been shown that the activity of intracellular adenosine kinase preferentially controls the activation of A1Rs, but the source of the adenosine activating A2ARs is unknown. We now show that ecto-5'-nucleotidase (CD73), the major enzyme able to convert extracellular AMP into adenosine, colocalizes with A2ARs in the basal ganglia. In addition to astrocytes, striatal CD73 is prominently localized to postsynaptic sites. Notably, CD73 coimmunoprecipitated with A2ARs and proximity ligation assays confirmed the close proximity of CD73 and A2ARs in the striatum. Accordingly, the cAMP formation in synaptosomes as well as the hypolocomotion induced by a novel A2AR prodrug that requires CD73 metabolization to activate A2ARs were observed in wild-type mice, but not in CD73 knock-out (KO) mice or A2AR KO mice. Moreover, CD73 KO mice displayed increased working memory performance and a blunted amphetamine-induced sensitization, mimicking the phenotype of global or forebrain-A2AR KO mice, as well as upon pharmacological A2AR blockade. These results show that CD73-mediated formation of extracellular adenosine is responsible for the activation of striatal A2AR function. This study points to CD73 as a new target that can fine-tune A2AR activity, and a novel therapeutic target to manipulate A2AR-mediated control of striatal function and neurodegeneration.

05/2012 | Glia   IF 6
Adenosine A2A receptors modulate glutamate uptake in cultured astrocytes and gliosomes.
Matos M, Augusto E, Santos-Rodrigues AD, Schwarzschild MA, Chen JF, Cunha RA, Agostinho P

Glutamate is the primary excitatory neurotransmitter in the central nervous system, where its toxic build-up leads to synaptic dysfunction and excitotoxic cell death that underlies many neurodegenerative diseases. Therefore, efforts have been made to understand the regulation of glutamate transporters, which are responsible for the clearance of extracellular glutamate. We now report that adenosine A(2A) receptors (A(2A) R) control the uptake of D-aspartate in primary cultured astrocytes as well as in an ex vivo preparation enriched in glial plasmalemmal vesicles (gliosomes) from adult rats, whereas A(1) R and A(3) R were devoid of effects. Thus, the acute exposure to the A(2A) R agonist, CGS 21680, inhibited glutamate uptake, an effect prevented by the A(2A) R antagonist, SCH 58261, and abbrogated in cultured astrocytes from A(2A) R knockout mice. Furthermore, the prolonged activation of A(2A) R lead to a cAMP/protein kinase A-dependent reduction of GLT-I and GLAST mRNA and protein levels, which leads to a sustained decrease of glutamate uptake. This dual mechanism of inhibition of glutamate transporters by astrocytic A(2A) R provides a novel candidate mechanism to understand the ability of A(2) (A) R to control synaptic plasticity and neurodegeneration, two conditions tightly associated with the control of extracellular glutamate levels by glutamate transporters.

2012 | j alzheimers dis   IF 3.9
Astrocytic adenosine A2A receptors control the amyloid-beta peptide-induced decrease of glutamate uptake.
Matos M, Augusto E, Machado NJ, dos Santos-Rodrigues A, Cunha RA, Agostinho P

Alzheimer's disease (AD) is characterized by a progressive cognitive impairment tightly correlated with the accumulation of amyloid-beta (Abeta) peptides (mainly Abeta(1-42)). There is a precocious disruption of glutamatergic synapses in AD, in line with an ability of Abeta to decrease astrocytic glutamate uptake. Accumulating evidence indicates that caffeine prevents the burden of AD, likely through the antagonism of A(2A) receptors (A(2A)R) which attenuates Abeta-induced memory impairment and synaptotoxicity. Since A(2A)R also modulate astrocytic glutamate uptake, we now tested if A(2A)R blockade could prevent the decrease of astrocytic glutamate uptake caused by Abeta. In cultured astrocytes, Abeta(1-42). (1 muM for 24 hours) triggered an astrogliosis typified by an increased density of GFAP, which was mimicked by the A(2A)R agonist, CGS 26180 (30 nM), and prevented by the A(2A)R antagonist, SCH 58261 (100 nM). Abeta1-42 also decreased D-aspartate uptake by 28 +/- 4%, an effect abrogated upon genetic inactivation or pharmacological blockade of A(2A)R. In accordance with the long term control of glutamate transporter expression by A(2A)R, Abeta(1-42). enhanced the expression and density of astrocytic A(2A)R and decreased GLAST and GLT-I expression in astrocytes from wild type, but not from A(2A)R knockout mice. This impact of Abeta(1-42). on glutamate transporters and uptake, dependent on A(2A)R function, was also confirmed in an ex vivo astrocyte preparation (gliosomes) from rats intracerebroventricularly (icv) injected with Abeta(1-42). . These results provide the first demonstration for a direct key role of astrocytic A(2A)R in the ability of Abeta-induced impairment of glutamate uptake, which may underlie glutamatergic synaptic dysfunction and excitotoxicity in AD.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by excessive deposition of amyloid-beta (Abeta) peptides in the brain. One of the earliest neuropathological changes in AD is the presence of a high number of reactive astrocytes at sites of Abeta deposition. Disturbance of glutamatergic neurotransmission and consequent excitotoxicity is also believed as implicated in the progression of this dementia. Therefore, the study of astrocyte responses to Abeta, the main cellular type involved in the maintenance of synaptic glutamate concentrations, is crucial for understanding the pathogenesis of AD. This study aims to investigate the effect of Abeta on the astrocytic glutamate transporters, glutamate transporter-1 (GLT-1) and glutamate-aspartate transporter (GLAST), and their relative participation to glutamate clearance. In addition we have also investigated the involvement of mitogen-activated protein (MAP) kinases in the modulation of GLT-1 and GLAST levels and activity and the putative contribution of oxidative stress induced by Abeta to the astrocytic glutamate transport function. Therefore, we used primary cultures of rat brain astrocytes exposed to Abeta synthetic peptides. The data obtained show that Abeta(1-40) peptide decreased astroglial glutamate uptake capacity in a non-competitive mode of inhibition, assessed in terms of tritium radiolabeled d-aspartate (d-[(3)H]aspartate) transport. The activity of GLT-1 seemed to be more affected than that of GLAST, and the levels of both transporters were decreased in Abeta(1-40)-treated astrocytes. We demonstrated that MAP kinases, extracellular signal-regulated kinase (ERK), p38 and c-Jun N-terminal kinase, were activated in an early phase of Abeta(1-40) treatment and the whole pathways differentially modulated the glutamate transporters activity/levels. Moreover it was shown that oxidative stress induced by Abeta(1-40) may lead to the glutamate uptake impairment observed. Taken together, our results suggest that Abeta peptide downregulates the astrocytic glutamate uptake capacity and this effect may be in part mediated by oxidative stress and the differential activity and complex balance between the MAP kinase signaling pathways.