title: Enhancement of NMDA receptor-mediated excitatory postsynaptic currents by gp120-treated macrophages: implications for HIV-1-associated neuropathology.
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.
authors: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
authors: Jianming
authors: J
authors: Yang
authors: Dehui
authors: D
authors: Hu
authors: Jianxun
authors: J
authors: Xia
authors: Jianuo
authors: J
authors: Liu
authors: Gang
authors: G
authors: Zhang
authors: Howard E
authors: HE
authors: Gendelman
authors: Nawal M
authors: NM
authors: Boukli
authors: Huangui
authors: H
authors: Xiong
mesh_terms: D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D005260:Female; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D008297:Male; D009924:Organ Culture Techniques; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D015699:HIV Envelope Protein gp120; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; C514793:gp120 protein, Human immunodeficiency virus 1
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