Ciliary neurotrophic factor activates astrocytes, redistributes their glutamate transporters GLAST and GLT-1 to raft microdomains, and improves glutamate handling in vivo.
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 [(18)F]-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.
Escartin
Carole
C
Commissariat à l'Energie Atomique, Centre National de la Recherche Scientifique, Unité de Recherche Associée 2210, 91401 Orsay, France.
Brouillet
Emmanuel
E
Gubellini
Paolo
P
Trioulier
Yaël
Y
Jacquard
Carine
C
Smadja
Claire
C
Knott
Graham W
GW
Kerkerian-Le Goff
Lydia
L
Déglon
Nicole
N
Hantraye
Philippe
P
Bonvento
Gilles
G
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D020934:Ciliary Neurotrophic Factor / Q000235:genetics / Q000494:pharmacology*; D018920:Coculture Techniques; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology*; D027341:Excitatory Amino Acid Transporter 1 / Q000187:drug effects / Q000502:physiology*; D027342:Excitatory Amino Acid Transporter 2 / Q000187:drug effects / Q000502:physiology*; D005822:Genetic Vectors; D018698:Glutamic Acid / Q000502:physiology*; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008297:Male; D021962:Membrane Microdomains / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew
D020934:Ciliary Neurotrophic Factor; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D018698:Glutamic Acid