Ciliary Neurotrophic Factor Protects Striatal Neurons against Excitotoxicity by Enhancing Glial Glutamate Uptake

Corinne Beurrier,Carole Escartin,Paolo Gubellini,Gilles Bonvento,Mathilde Faideau,Khaled-Ezaheir Bennouar,Lydia Kerkerian-Le Goff,Colin Combs

doi:10.1371/journal.pone.0008550

Abstract

Ciliary neurotrophic factor (CNTF) is a potent neuroprotective cytokine in different animal models of glutamate-induced excitotoxicity, although its action mechanisms are still poorly characterized. We tested the hypothesis that an increased function of glial glutamate transporters (GTs) could underlie CNTF-mediated neuroprotection. We show that neuronal loss induced by in vivo striatal injection of the excitotoxin quinolinic acid (QA) was significantly reduced (by ∼75%) in CNTF-treated animals. In striatal slices, acute QA application dramatically inhibited corticostriatal field potentials (FPs), whose recovery was significantly higher in CNTF rats compared to controls (∼40% vs. ∼7%), confirming an enhanced resistance to excitotoxicity. The GT inhibitor dl-threo-β-benzyloxyaspartate greatly reduced FP recovery in CNTF rats, supporting the role of GT in CNTF-mediated neuroprotection. Whole-cell patch-clamp recordings from striatal medium spiny neurons showed no alteration of basic properties of striatal glutamatergic transmission in CNTF animals, but the increased effect of a low-affinity competitive glutamate receptor antagonist (γ-d-glutamylglycine) also suggested an enhanced GT function. These data strongly support our hypothesis that CNTF is neuroprotective via an increased function of glial GTs, and further confirms the therapeutic potential of CNTF for the clinical treatment of progressive neurodegenerative diseases involving glutamate overflow.

Highlights

Ciliary neurotrophic factor (CNTF) is a neurotrophic cytokine belonging to the interleukin-6 type family
We have recently shown that CNTFactivated astrocytes display marked phenotypic and molecular changes associated with an improved handling of extracellular glutamate in the rat striatum [12]
We show that CNTF neuroprotective effects against glutamate excitotoxicity do not rely on a direct action on striatal medium-sized spiny neurons (MSNs) and glutamate transmission, but are mediated by an enhanced glutamate uptake in activated astrocytes

Summary

Introduction

Ciliary neurotrophic factor (CNTF) is a neurotrophic cytokine belonging to the interleukin-6 type family. A phase I clinical trial confirmed the safety of local brain administration of encapsulated cells genetically engineered to produce CNTF and reported a recovery of somatosensory evoked potentials in patient implanted with capsules releasing the largest amount of CNTF [8]. Despite these encouraging results, the mechanisms mediating CNTF neuroprotective effect are still unclear. We have recently shown that CNTFactivated astrocytes display marked phenotypic and molecular changes associated with an improved handling of extracellular glutamate in the rat striatum [12] We suggested that such effect could be mediated by an increased function of astrocyte glutamate transporters (GTs), GLAST and GLT-1. Using lentivirus-mediated CNTF overexpression in the rat striatum, whole-cell patch-clamp and extracellular electrophysiological recordings on corticostriatal slices, we provide evidence that CNTF neuroprotective effects against QA are mediated through an enhanced glutamate uptake by activated astrocytes

Methods

Results

Conclusion