Fractalkine (CX3CL1) enhances hippocampal N-methyl-d-aspartate receptor (NMDAR) function via d-serine and adenosine receptor type A2 (A2AR) activity

Journal of Neuroinflammation

Laura Maggi²  Cristina Limatola³  Maria Amalia Di Castro²  Gloria Cristalli¹  Giuseppina Chece²  Letizia Antonilli²  Maria Scianni² 

[1]School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, Camerino, Italy

[2]Institute Pasteur-Cenci Bolognetti Foundation, Department of Physiology and Pharmacology, University Sapienza, Rome, Italy

[3]IRCCS Neuromed, Pozzilli, Italy

关键词: Adenosine receptors;    D-serine;    Hippocampus;    Microglia;    NMDAR;    CX₃CL1;   

Others  :  1152136
DOI  :  10.1186/1742-2094-10-108

 received in 2013-01-07, accepted in 2013-05-28,  发布年份 2013

【 摘 要 】

Background

N-Methyl-D-aspartate receptors (NMDARs) play fundamental roles in basic brain functions such as excitatory neurotransmission and learning and memory processes. Their function is largely regulated by factors released by glial cells, including the coagonist D-serine. We investigated whether the activation of microglial CX₃CR1 induces the release of factors that modulate NMDAR functions.

Methods

We recorded the NMDAR component of the field excitatory postsynaptic potentials (NMDA-fEPSPs) elicited in the CA1 stratum radiatum of mouse hippocampal slices by Shaffer collateral stimulation and evaluated D-serine content in the extracellular medium of glial primary cultures by mass spectrometry analysis.

Results

We demonstrated that CX₃CL1 increases NMDA-fEPSPs by a mechanism involving the activity of the adenosine receptor type A2 (A_2AR) and the release of the NMDAR coagonist D-serine. Specifically (1) the selective A_2AR blocker 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH58261) and the genetic ablation of A_2AR prevent CX₃CL1 action while the A_2AR agonist 5-(6-amino-2-(phenethylthio)-9H-purin-9-yl)-N-ethyl-3,4-dihydroxytetrahydrofuran-2-carboxamide (VT7) mimics CX₃CL1 effect, and (2) the selective blocking of the NMDAR glycine (and D-serine) site by 5,7-dicholorokynurenic acid (DCKA), the enzymatic degradation of D-serine by D-amino acid oxidase (DAAO) and the saturation of the coagonist site by D-serine, all block the CX₃CL1 effect. In addition, mass spectrometry analysis demonstrates that stimulation of microglia and astrocytes with CX₃CL1 or VT7 increases D-serine release in the extracellular medium.

Conclusions

CX₃CL1 transiently potentiates NMDAR function though mechanisms involving A_2AR activity and the release of D-serine.

【 授权许可】

   
2013 Scianni et al.; licensee BioMed Central Ltd.

【 图 表 】

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