CXCR4 and NMDA Receptors Are Functionally Coupled in Rat Hippocampal Noradrenergic and Glutamatergic Nerve Endings

J Neuroimmune Pharmacol. 2016 Dec;11(4):645-656. doi: 10.1007/s11481-016-9677-6. Epub 2016 May 5.


Previous studies had shown that the HIV-1 capsidic glycoprotein gp120 (strain IIIB) modulates presynaptic release-regulating NMDA receptors on noradrenergic and glutamatergic terminals. This study aims to assess whether the chemokine CXC4 receptors (CXCR4s) has a role in the gp120-mediated effects. The effect of CXCL12, the endogenous ligand at CXCR4, on the NMDA-mediated releasing activity was therefore investigated. Rat hippocampal synaptosomes were preloaded with [3H]noradrenaline ([3H]NA) or [3H]D-aspartate ([3H]D-Asp) and acutely exposed to CXCL12, to NMDA or to both agonists. CXCL12, inactive on its own, facilitated the NMDA-evoked tritium release. The NMDA antagonist MK-801 abolished the NMDA/CXCL12-evoked tritium release of both radiolabelled tracers, while the CXCR4 antagonist AMD 3100 halved it, suggesting that rat hippocampal nerve endings possess presynaptic release-regulating CXCR4 receptors colocalized with NMDA receptors. Accordingly, Western blot analysis confirmed the presence of CXCR4 proteins in synaptosomal plasmamembranes. In both synaptosomal preparations, CXCL12-induced facilitation of NMDA-mediated release was dependent upon PLC-mediated src-induced events leading to mobilization of Ca2+ from intraterminal IP3-sensitive stores Finally, the gp120-induced facilitation of NMDA-mediated release of [3H]NA and [3H]D-Asp was prevented by AMD 3100. We propose that CXCR4s are functionally coupled to NMDA receptors in rat hippocampal noradrenergic and glutamatergic terminals and account for the gp120-induced modulation of the NMDA-mediated central effects. The NMDA/CXCR4 cross-talk could have a role in the neuropsychiatric symptoms often observed in HIV-1 positive patients.

Keywords: CXCL12; CXCR4; Glutamate; NMDA receptor; Noradrenaline; gp120.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Neurons / drug effects
  • Adrenergic Neurons / physiology*
  • Animals
  • Chemokine CXCL12 / pharmacology
  • Dose-Response Relationship, Drug
  • Glutamic Acid / physiology*
  • Hippocampus / drug effects
  • Hippocampus / physiology*
  • N-Methylaspartate / pharmacology
  • Nerve Endings / drug effects
  • Nerve Endings / physiology*
  • Protein Binding / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, CXCR4 / agonists
  • Receptors, CXCR4 / physiology*
  • Receptors, N-Methyl-D-Aspartate / agonists
  • Receptors, N-Methyl-D-Aspartate / physiology*


  • CXCL12 protein, rat
  • Chemokine CXCL12
  • Cxcr4 protein, rat
  • Receptors, CXCR4
  • Receptors, N-Methyl-D-Aspartate
  • Glutamic Acid
  • N-Methylaspartate