Activity of adenosine receptors type 1 is required for CX 3CL1-mediated neuroprotection and neuromodulation in hippocampal neurons

Clotilde Lauro, Silvia Di Angelantonio, Raffaela Cipriani, Fabrizia Sobrero, Letizia Antonilli, Valentina Brusadin, Davide Ragozzino, Cristina Limatola

Research output: Contribution to journalArticlepeer-review

Abstract

The chemokine fractalkine (CX 3CL1) is constitutively expressed by central neurons, regulating microglial responses including chemotaxis, activation, and toxicity. Through the activation of its own specific receptor, CX 3CR1, CX 3CL1 exerts both neuroprotection against glutamate (GIu) toxicity and neuromodulation of the glutamatergic synaptic transmission in hippocampal neurons. Using cultured hippocampal neuronal cell preparations, obtained from CX 3CRl -/- (CX 3CR1 GFP/GFP) mice, we report that these same effects are mimicked by exposing neurons to a medium conditioned with CX 3CL1- treated mouse microglial cell line BV2 (BV2-st medium). Furthermore, CX 3CL1-induced neuroprotection from Glu toxicity is mediated through the adenosine receptor 1 (AR 1), being blocked by neuronal cell preparations treatment with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), a specific inhibitor of AR and mimicked by both adenosine and the specific AR, agonist 2-chloro-N 6-cyclopentyladenosine. Similarly, experiments from whole-cell patch-clamped hippocampal neurons in culture, obtained from CX 3CR1 +/+ mice, show that CX 3CL1-induced depression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-(AMPA-) type GIu receptor-mediated current (AMPA-current), is associated with AR, activity being blocked by DPCPX and mimicked by adenosine. Furthermore, BV2-st medium induced a similar AMPA-current depression in CX 3CR1 GFP/GFP hippocampal neurons and this depression was again blocked by DPCPX. We also report that CX 3CL1 induced a significant release of adenosine from microglial BV2 cells, as measured by HPLC analysis. We demonstrate that (i) CX 3CL1, along with AR 1, are critical players for counteracting Glu-mediated neurotoxicity in the brain and (ii) AR 1 mediates neuro-modulatory action of CX 3CL1 on hippocampal neurons.

Original languageEnglish
Pages (from-to)7590-7596
Number of pages7
JournalJournal of Immunology
Volume180
Issue number11
Publication statusPublished - 2008

ASJC Scopus subject areas

  • Immunology

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