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

J Neuroinflammation. 2013 Aug 27;10:108. doi: 10.1186/1742-2094-10-108.


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 (A2AR) and the release of the NMDAR coagonist D-serine. Specifically (1) the selective A2AR 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 A2AR prevent CX3CL1 action while the A2AR 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 A2AR activity and the release of D-serine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemokine CX3CL1 / metabolism*
  • Chromatography, Liquid
  • Excitatory Postsynaptic Potentials / physiology
  • Hippocampus / metabolism*
  • Mass Spectrometry
  • Mice
  • Mice, Inbred C57BL
  • Neuroglia / metabolism
  • Organ Culture Techniques
  • Patch-Clamp Techniques
  • Receptors, Adenosine A2 / metabolism*
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Serine / metabolism*


  • Chemokine CX3CL1
  • Cx3cl1 protein, mouse
  • Receptors, Adenosine A2
  • Receptors, N-Methyl-D-Aspartate
  • Serine