Enhancement of NMDA Receptor-Mediated Excitatory Postsynaptic Currents by gp120-Treated Macrophages: Implications for HIV-1-Associated Neuropathology
Journal of Neuroimmune Pharmacology(2013)
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 EPSC NMDAR . In contrast, control (untreated) MCM had limited effects on EPSC NMDAR . Testing NR2A NMDAR (NR2AR)-mediated EPSC (EPSC NR2AR ) and NR2B NMDAR (NR2BR)-mediated EPSC (EPSC NR2BR ) for MCM showed significant increased EPSC NR2BR when compared to EPSC NR2AR enhancement. When synaptic NR2AR-mediated EPSC was blocked by bath application of MK801 combined with low frequency stimulations, MCM retained its ability to enhance EPSC NMDAR evoked by stronger stimulations. This suggested that increase in EPSC NMDAR 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 EPSC NMDAR . 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.
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Key words
HIV-1gp120,Macrophages,NMDA receptors,EPSC,Neurotoxicity
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