title: Activity of adenosine receptors type 1 Is required for CX3CL1-mediated neuroprotection and neuromodulation in hippocampal neurons.
abstract: The chemokine fractalkine (CX(3)CL1) is constitutively expressed by central neurons, regulating microglial responses including chemotaxis, activation, and toxicity. Through the activation of its own specific receptor, CX(3)CR1, CX(3)CL1 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 CX(3)CR1(-/-) (CX(3)CR1(GFP/GFP)) mice, we report that these same effects are mimicked by exposing neurons to a medium conditioned with CX(3)CL1-treated mouse microglial cell line BV2 (BV2-st medium). Furthermore, CX(3)CL1-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(1), and mimicked by both adenosine and the specific AR(1) agonist 2-chloro-N(6)-cyclopentyladenosine. Similarly, experiments from whole-cell patch-clamped hippocampal neurons in culture, obtained from CX(3)CR1(+/+) mice, show that CX(3)CL1-induced depression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid- (AMPA-) type Glu receptor-mediated current (AMPA-current), is associated with AR(1) activity being blocked by DPCPX and mimicked by adenosine. Furthermore, BV2-st medium induced a similar AMPA-current depression in CX(3)CR1(GFP/GFP) hippocampal neurons and this depression was again blocked by DPCPX. We also report that CX(3)CL1 induced a significant release of adenosine from microglial BV2 cells, as measured by HPLC analysis. We demonstrate that (i) CX(3)CL1, along with AR(1), are critical players for counteracting Glu-mediated neurotoxicity in the brain and (ii) AR(1) mediates neuromodulatory action of CX(3)CL1 on hippocampal neurons.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti & Dipartimento di Fisiologia Umana e Farmacologia, Centro di Eccellenza BEMM, Università Sapienza, Roma.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Lauro
authors.forename: Silvia
authors.initials: S
authors.lastname: Di Angelantonio
authors.forename: Raffaela
authors.initials: R
authors.lastname: Cipriani
authors.forename: Fabrizia
authors.initials: F
authors.lastname: Sobrero
authors.forename: Letizia
authors.initials: L
authors.lastname: Antonilli
authors.forename: Valentina
authors.initials: V
authors.lastname: Brusadin
authors.forename: Davide
authors.initials: D
authors.lastname: Ragozzino
authors.forename: Cristina
authors.initials: C
authors.lastname: Limatola
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D054428:Chemokine CX3CL1 / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D014970:Xanthines / Q000494:pharmacology
chemical_list: D054428:Chemokine CX3CL1; D018696:Neuroprotective Agents; D058915:Purinergic P1 Receptor Antagonists; D018091:Receptors, AMPA; D018047:Receptors, Purinergic P1; D014970:Xanthines; C051360:1,3-dipropyl-8-cyclopentylxanthine