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Activity of Adenosine Receptors Type 1 Is Required for CX₃CL1-Mediated Neuroprotection and Neuromodulation in Hippocampal Neurons¹

Clotilde Lauro^*, Silvia Di Angelantonio^*, Raffaela Cipriani^*, Fabrizia Sobrero^*, Letizia Antonilli^*, Valentina Brusadin, Davide Ragozzino^*, and Cristina Limatola^2,*,

^* Istituto Pasteur-Fondazione Cenci Bolognetti & Dipartimento di Fisiologia Umana e Farmacologia, Centro di Eccellenza BEMM, Università Sapienza, Roma, Universitá di Bari, and Neuromed Istituto Ricovero & Cura a Carattere Scientifico via Atinese 18, Venafro, Italy

The chemokine fractalkine (CX₃CL1) is constitutively expressed by central neurons, regulating microglial responses including chemotaxis, activation, and toxicity. Through the activation of its own specific receptor, CX₃CR1, CX₃CL1 exerts both neuroprotection against glutamate (Glu) toxicity and neuromodulation of the glutamatergic synaptic transmission in hippocampal neurons. Using cultured hippocampal neuronal cell preparations, obtained from CX₃CR1^–/– (CX₃CR1^GFP/GFP) mice, we report that these same effects are mimicked by exposing neurons to a medium conditioned with CX₃CL1-treated mouse microglial cell line BV2 (BV2-st medium). Furthermore, CX₃CL1-induced neuroprotection from Glu toxicity is mediated through the adenosine receptor 1 (AR₁), being blocked by neuronal cell preparations treatment with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), a specific inhibitor of AR₁, and mimicked by both adenosine and the specific AR₁ agonist 2-chloro-N⁶-cyclopentyladenosine. Similarly, experiments from whole-cell patch-clamped hippocampal neurons in culture, obtained from CX₃CR1^+/+ mice, show that CX₃CL1-induced depression of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid- (AMPA-) type Glu receptor-mediated current (AMPA-current), is associated with AR₁ activity being blocked by DPCPX and mimicked by adenosine. Furthermore, BV2-st medium induced a similar AMPA-current depression in CX₃CR1^GFP/GFP hippocampal neurons and this depression was again blocked by DPCPX. We also report that CX₃CL1 induced a significant release of adenosine from microglial BV2 cells, as measured by HPLC analysis. We demonstrate that (i) CX₃CL1, along with AR₁, are critical players for counteracting Glu-mediated neurotoxicity in the brain and (ii) AR₁ mediates neuromodulatory action of CX₃CL1 on hippocampal neurons.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Ministry of Health (to Dr. Fabrizio Eusebi, Rome University, Sapienza) and by the Ministry of University and Research (Programmi di ricercadi Rilevante Interesse Nazionale to C.L.).

² Address correspondence and reprint requests Dr. Cristina Limatola, Dipartimento di Fisiologia Umana e Farmacologia, Piazzale A. Moro 5, I00185 Roma. E-mail address: cristina.limatola{at}uniroma1.it

³ Abbreviations used in this paper: AR, adenosine receptor; Glu, glutamate; DPCPX, 1,3-dipropyl-8-cyclopentylxanthine; CCPA, 2-chloro-N⁶-cyclopentyladenosine; AMPA, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; EGFP, enhanced green fluorescent protein; NES, normal external solution.

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