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 ability to affact NMDAR-mediated excitatory postsynaptic currents (EPSCNMDAR) 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 (<3kD) to medium (3-10kD) 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.

HIV-1 Glycoprotein 120 Enhancement of N-Methyl-D-Aspartate NMDA Receptor-Mediated Excitatory Postsynaptic Currents: Implications for HIV-1-Associated Neural Injury

“…Further studies unraveled that gp120 increased both EPSC NR2AR and EPSC NR2BR with significant stronger effect on EPSC NR2BR than EPSC NR2AR . Using an experimental protocol to block synaptic NMDARs (Thomas et al, 2006; Yang et al, 2013), we revealed that gp120 significantly increased extra-synaptic EPSC NMDAR which was blocked by a NR2BR antagonist ifenprodil, demonstrating for the first time, to our knowledge, that gp120 acts on extra-synaptic NR2BRs.…”

“…Gp120 is toxic to neural cells and can promote detrimental alterations on synaptic transmission and plasticity, leading to an impairment of cognitive function (Dreyer and Lipton, 1995; Lannuzel et al, 1997; Dong and Xiong, 2006). Studies have shown that gp120 causes neuronal damage through multiple pathways including direct interactions with neurons via cell surface receptors and ion channels (Lannuzel et al, 1995; Medina et al, 1999) or by stimulating mononuclear phagocytes (brain perivascular macrophages and microglia) release of neurotoxic substances, the so-called indirect mechanism, which in turn act on neuronal cells leading to neuronal damage (Xiong et al, 2003; O'Donnell et al, 2006; Yang et al, 2013). It is widely accepted that the major pathway by which gp120 causes neuronal injury is via activation of NMDARs and resultant raising intracellular calcium concentration (Barks et al, 1995; Kaul, 2008).…”

“…It has been shown that the HIV-1-associated neuronal injury and death can be attenuated or prevented by NMDAR antagonists, suggesting an involvement of NMDAR in HIV-1-associated neurotoxicity (Muller et al, 1996; Kaul et al, 2001; Anderson et al, 2004; O'Donnell et al, 2006; Shin et al, 2012). However, most of previous studies have focused on an indirect mechanism for HIV-1/gp120-assoociated neurotoxicity, that is, HIV-1-infected or gp120-stimulated mononuclear phagocytes release soluble molecules leading to NMDAR activation and resultant neuronal injury (O'Donnell et al, 2006; Yang et al, 2013). Relative fewer studies have investigated direct interactions of gp120 and NMDAR-mediated synaptic transmission.…”

HIV-1 Tat-Induced Changes in Synaptically-Driven Network Activity Adapt During Prolonged Exposure

“…Furthermore, this approach enables recording from single cells and from networks of many cells simultaneously. In addition to Tat [13, 36], many HIV-associated neurotoxins, while acting through distinct upstream pathways, potentiate NMDAR mediated Ca 2+ influx including: gp120 [20, 37–39], inflammatory cytokines [40, 41] and excitotoxins [42]. Thus, results obtained with Tat may extend to other neurotoxins.…”

HIV-1 gp120Bal down-Regulates Phosphorylated NMDA Receptor Subunit 1 in Cortical Neurons via Activation of Glutamate and Chemokine Receptors

“…In addition to synaptic degeneration, HIV-1 proteins may also interfere with synaptic activity (Haughey and Mattson, 2002; Kasyanov et al , 2006; Krogh et al , 2014; Nath et al , 1996; Tovar et al , 2013; Xu et al , 2011). For instance, gp120 was shown to activate N-methyl D-aspartate receptor (NMDAR), and this could induce synaptic damage (Gemignani et al , 2000; Kaul and Lipton, 1999; Lipton, 1992; Pattarini et al , 1998; Toggas et al , 1996; Viviani et al , 2006; Yang et al , 2013). Interestingly, T-cell-tropic (T-tropic) gp120 IIIB promoted trafficking and surface clustering of NMDA receptors in membrane microdomains in cultured hippocampal neurons.…”