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The Journal of Neuroscience, October 11, 2006, 26(41):10488-10498; doi:10.1523/JNEUROSCI.3192-06.2006

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Development/Plasticity/Repair
Chemokine Fractalkine/CX₃CL1 Negatively Modulates Active Glutamatergic Synapses in Rat Hippocampal Neurons

Davide Ragozzino,^1,2 * Silvia Di Angelantonio,^1 * Flavia Trettel,¹ Cristina Bertollini,¹ Laura Maggi,¹ Cornelius Gross,³ Israel F. Charo,⁴ Cristina Limatola,^1,2 and Fabrizio Eusebi^1,2

¹Istituto Pasteur-Fondazione Cenci Bolognetti and Dipartimento di Fisiologia Umana e Farmacologia, Università La Sapienza, Centro di Eccellenza BEMM, 00185 Roma, Italy, ²Neuromed, 86077 Pozzilli, Italy, ³European Molecular Biology Laboratory, Mouse Biology Unit, 00016 Monterotondo, Italy, and ⁴Gladstone Institute of Cardiovascular Disease, San Francisco, California 94141

Correspondence should be addressed to Dr. Davide Ragozzino, Istituto Fisiologia Umana, Piazzale A. Moro 5, I00185 Roma, Italy. Email: davide.ragozzino{at}uniroma1.it

We examined the effects of the chemokine fractalkine (CX₃CL1) on EPSCs evoked by electrical stimulation of Schaffer collaterals in patch-clamped CA1 pyramidal neurons from rat hippocampal slices. Acute application of CX₃CL1 caused a sustained reduction of EPSC amplitude, with partial recovery after washout. CX₃CL1-induced EPSC depression is postsynaptic in nature, because paired-pulse ratio was maintained, amplitude distribution of spontaneous excitatory postsynaptic currents shifted to lower values, and whole-cell current responses to AMPA were reversibly inhibited. EPSC depression by CX₃CL1 is mediated by CX₃CL1 receptor (CX₃CR1), because CX₃CL1 was unable to influence EPSC amplitude in CA1 pyramidal neurons from CX₃CR1 knock-out mice. CX₃CL1-induced depression of both EPSC and AMPA current was not observed in the absence of afferent fiber stimulation or AMPA receptor activation, respectively, indicating the requirement of sustained receptor activity for its development. Findings obtained from hippocampal slices, cultured hippocampal neurons, and transfected human embryonic kidney cells indicate that a Ca²⁺-, cAMP-, and phosphatase-dependent process is likely to modulate CX₃CL1 effects because of the following: (1) CX₃CL1-induced depression was antagonized by intracellular BAPTA, 8Br-cAMP, phosphatase inhibitors, and pertussis toxin (PTX); (2) CX₃CL1 inhibited forskolin-induced cAMP formation sensitive to PTX; and (3) CX₃CL1 inhibited forskolin-induced Ser845 GluR1 phosphorylation, which was sensitive to PTX and dependent on Ca²⁺ and phosphatase activity. Together, these findings indicate that CX₃CL1 negatively modulates AMPA receptor function at active glutamatergic synapses through cell-signaling pathways by influencing the balance between kinase and phosphatase activity.

Key words: AMPA receptors; hippocampal slices; GluR1; phosphorylation; chemokines; EPSC depression; adenylate cyclase

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Received July 11, 2005; revised Aug. 10, 2006; accepted Aug. 10, 2006.

Correspondence should be addressed to Dr. Davide Ragozzino, Istituto Fisiologia Umana, Piazzale A. Moro 5, I00185 Roma, Italy. Email: davide.ragozzino{at}uniroma1.it

This article has been cited by other articles:

				C. Lauro, S. Di Angelantonio, R. Cipriani, F. Sobrero, L. Antonilli, V. Brusadin, D. Ragozzino, and C. Limatola Activity of Adenosine Receptors Type 1 Is Required for CX3CL1-Mediated Neuroprotection and Neuromodulation in Hippocampal Neurons J. Immunol., June 1, 2008; 180(11): 7590 - 7596. [Abstract] [Full Text] [PDF]

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