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The Journal of Neuroscience, May 31, 2006, 26(22):5978-5989; doi:10.1523/JNEUROSCI.0302-06.2006

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Development/Plasticity/Repair
Ciliary Neurotrophic Factor Activates Astrocytes, Redistributes Their Glutamate Transporters GLAST and GLT-1 to Raft Microdomains, and Improves Glutamate Handling In Vivo

Carole Escartin,¹ Emmanuel Brouillet,¹ Paolo Gubellini,³ Yaël Trioulier,¹ Carine Jacquard,¹ Claire Smadja,⁴ Graham W. Knott,⁵ Lydia Kerkerian-Le Goff,³ Nicole Déglon,^2,6 Philippe Hantraye,^1,2,6 and Gilles Bonvento¹

¹Commissariat à l'Energie Atomique (CEA), Centre National de la Recherche Scientifique (CNRS) Unité de Recherche Associée 2210 and ²Unité d'imagerie isotopique, biochimique et pharmacologique, Service Hospitalier Frédéric Joliot, 91401 Orsay, France, ³Institut de Biologie du développement de Marseille Luminy, CNRS Unité Mixte de Recherche 6216, Université de la Méditerranée, 13284 Marseille, France, ⁴Jeune Equipe 2495, Faculté de Pharmacie, Université Paris-Sud 11, 92296 Châtenay-Malabry, France, ⁵Département de Biologie Cellulaire et Morphologie, Université de Lausanne, CH-1005 Lausanne, Switzerland, and ⁶Molecular Imaging Research Center CEA, 92265 Fontenay-Aux-Roses, France

Correspondence should be addressed to Dr. Gilles Bonvento, Service Hospitalier Frédéric Joliot, Commissariat à l'Energie Atomique, Centre National de la Recherche Scientifique Unité de Recherche Associée 2210, 4 place du général Leclerc, 91401 Orsay, France. Email: bonvento{at}shfj.cea.fr

To study the functional role of activated astrocytes in glutamate homeostasis in vivo, we used a model of sustained astrocytic activation in the rat striatum through lentiviral-mediated gene delivery of ciliary neurotrophic factor (CNTF). CNTF-activated astrocytes were hypertrophic, expressed immature intermediate filament proteins and highly glycosylated forms of their glutamate transporters GLAST and GLT-1. CNTF overexpression produced a redistribution of GLAST and GLT-1 into raft functional membrane microdomains, which are important for glutamate uptake. In contrast, CNTF had no detectable effect on the expression of a number of neuronal proteins and on the spontaneous glutamatergic transmission recorded from striatal medium spiny neurons. These results were replicated in vitro by application of recombinant CNTF on a mixed neuron/astrocyte striatal culture. Using microdialysis in the rat striatum, we found that the accumulation of extracellular glutamate induced by quinolinate (QA) was reduced threefold with CNTF. In line with this result, CNTF significantly increased QA-induced [¹⁸F]-fluoro-2-deoxyglucose uptake, an indirect index of glutamate uptake by astrocytes. Together, these data demonstrate that CNTF activation of astrocytes in vivo is associated with marked phenotypic and molecular changes leading to a better handling of increased levels of extracellular glutamate. Activated astrocytes may therefore be important prosurvival agents in pathological conditions involving defects in glutamate homeostasis.

Key words: activated astrocytes; CNTF; glutamate transporters; rafts; excitotoxicity; glucose uptake

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Received Aug. 23, 2005; revised April 24, 2006; accepted April 24, 2006.

Correspondence should be addressed to Dr. Gilles Bonvento, Service Hospitalier Frédéric Joliot, Commissariat à l'Energie Atomique, Centre National de la Recherche Scientifique Unité de Recherche Associée 2210, 4 place du général Leclerc, 91401 Orsay, France. Email: bonvento{at}shfj.cea.fr

This article has been cited by other articles:

				M. I. Gonzalez, E. Krizman-Genda, and M. B. Robinson Caveolin-1 Regulates the Delivery and Endocytosis of the Glutamate Transporter, Excitatory Amino Acid Carrier 1 J. Biol. Chem., October 12, 2007; 282(41): 29855 - 29865. [Abstract] [Full Text] [PDF]

				C. Escartin, K. Pierre, A. Colin, E. Brouillet, T. Delzescaux, M. Guillermier, M. Dhenain, N. Deglon, P. Hantraye, L. Pellerin, et al. Activation of Astrocytes by CNTF Induces Metabolic Plasticity and Increases Resistance to Metabolic Insults J. Neurosci., July 4, 2007; 27(27): 7094 - 7104. [Abstract] [Full Text] [PDF]

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