Enhancement of NMDA receptor-mediated excitatory postsynaptic currents by gp120-treated macrophages: Implications for HIV-1-associated neuropathology

Jianming Yang, Dehui Hu, Jianxun Xia, Jianuo Liu, Gang Zhang, Howard E. Gendelman, Nawal M. Boukli, Huangui Xiong

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

A plethora of prior studies has linked HIV-1-infected and immune activated brain mononuclear phagocytes (MP; blood borne macrophages and microglia) to neuronal dysfunction. These are modulated by N-methyl-D-aspartate receptor (NMDAR) antagonists and supporting their relevance for HIV-1-associated nervous system disease. The role of NMDAR subsets in HIV-1-induced neuronal injury, nonetheless, is poorly understood. To this end, we investigated conditioned media from HIV-1gp120-treated human monocyte-derived-macrophages (MDM) for its abilities to affect NMDAR-mediated excitatory postsynaptic currents (EPSC NMDAR) in rat hippocampal slices. Bath application of gp120-treated MDM-conditioned media (MCM) produced an increase of EPSCNMDAR. In contrast, control (untreated) MCM had limited effects on EPSCNMDAR. Testing NR2A NMDAR (NR2AR)-mediated EPSC (EPSCNR2AR) and NR2B NMDAR (NR2BR)-mediated EPSC (EPSCNR2BR) for MCM showed significant increased EPSCNR2BR when compared to EPSCNR2AR enhancement. When synaptic NR2AR-mediated EPSC was blocked by bath application of MK801 combined with low frequency stimulations, MCM retained its ability to enhance EPSCNMDAR evoked by stronger stimulations. This suggested that increase in EPSCNMDAR was mediated, in part, through extra-synaptic NR2BR. Further analyses revealed that the soluble factors with low (<3 kD) to medium (3-10 kD) molecular weight mediated the observed increases in EPSCNMDAR. The link between activation of NR2BRs and HIV-1gp120 MCM for neuronal injury was demonstrated by NR2BR but not NR2AR blockers. Taken together, these results indicate that macrophage secretory products induce neuronal injury through extra-synaptic NR2BRs.

Original languageEnglish (US)
Pages (from-to)921-933
Number of pages13
JournalJournal of Neuroimmune Pharmacology
Volume8
Issue number4
DOIs
StatePublished - Sep 2013

Keywords

  • EPSC
  • HIV-1gp120
  • Macrophages
  • NMDA receptors
  • Neurotoxicity

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Immunology and Allergy
  • Immunology
  • Pharmacology

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