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Updated: May 11, 2026
A Rat Model of EcoHIV Brain Infection
Published on: January 21, 2021
Enhancement of NMDA receptor-mediated excitatory postsynaptic currents by gp120-treated macrophages: implications for
Jianming Yang1, Dehui Hu, Jianxun Xia
1Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
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.
Insights
HIV-1 gp120 in macrophages releases factors that increase N-methyl-D-aspartate receptor (NMDAR) activity, particularly through extra-synaptic NR2B subunits, contributing to neuronal injury in HIV-1-associated nervous system disease.
Area of Science:
- Neuroscience
- Immunology
- Virology
Background:
- HIV-1 infection impacts the central nervous system, causing neuronal dysfunction.
- Brain mononuclear phagocytes (MP), including macrophages and microglia, are implicated in HIV-1-associated neurotoxicity.
- N-methyl-D-aspartate receptors (NMDARs) are crucial for synaptic function and are modulated by factors relevant to HIV-1 nervous system disease.
Purpose of the Study:
- To investigate the role of NMDAR subsets in HIV-1-induced neuronal injury.
- To determine how conditioned media from HIV-1 gp120-treated macrophages affects NMDAR-mediated currents.
- To identify the specific NMDAR subunits and factors involved in macrophage-induced neurotoxicity.
Main Methods:
- Prepared conditioned media from human monocyte-derived macrophages (MDM) treated with HIV-1 gp120.
- Applied conditioned media to rat hippocampal slices to measure NMDAR-mediated excitatory postsynaptic currents (EPSC(NMDAR)).
- Differentiated between NR2A and NR2B NMDAR contributions and analyzed molecular weights of active factors.
Main Results:
- Conditioned media from gp120-treated MDM significantly increased EPSC(NMDAR) compared to controls.
- The enhancement was primarily mediated by NR2B NMDARs, particularly extra-synaptic ones.
- Low to medium molecular weight soluble factors from macrophages were responsible for increasing EPSC(NMDAR).
- Blocking NR2B, but not NR2A, subunits prevented MCM-induced neuronal injury.
Conclusions:
- Macrophage secretory products, stimulated by HIV-1 gp120, induce neuronal injury.
- Extra-synaptic NR2B NMDARs are key mediators of this HIV-1-associated neurotoxicity.
- Understanding these mechanisms could inform therapeutic strategies for HIV-1 nervous system disease.
