Synaptic N-methyl-D-aspartic acid (NMDA) receptors (NMDARs), composed, in large part, of NR2A-containing NMDARs (NR2ARs), promote cell survival, whereas extrasynaptic NMDARs, NR2B-containing NMDARs (NR2BRs), induce cell death. It is known that a host of macrophage inflammatory and viral products engage NMDARs, but there is very limited information available on how these receptors can be """"""""best"""""""" utilized for optimal therapeutic benefit. To this end we seek funds to assess the role of HIV-1-infected and immune competent mononuclear phagocytes (MPs, brain perivascular macrophages and microglia) to affect extrasynaptic NR2BRs. MPs are the natural virus target cells and the key to neuronal dysfunction in HIV-1- associated neurocognitive disorders (HAND). Immunocytochemical, pharmacological and electrophysiological techniques will examine the role of extrasynaptic NR2BRs in HIV-1 infected MP-induced neuronal dysfunction and resultant cognitive impairment in laboratory and animal models of human disease. First, we will examine direct activation of NR2BRs by HIV-1 infected MP and resultant neurotoxic activity. Second, we will investigate the role of NR2BRs in HIV-1 infected MP-induced alteration of synaptic transmission and plasticity. Third, we will study whether HIV-1 infected MP-induced, NR2BR-mediated alteration of cellular and synaptic physiology contributes to HAND, and to explore potential protective effects of NR2BR antagonists in a relevant murine model of HIV disease. Overall, these studies are focused toward not only understanding the role that the subtype and location of NMDARs might play in HAND, but also on developing more realistic means to harness these pathways for therapeutic benefit. If successful, these studies will provide a proper roadmap for expected efficacy of NMDAR antagonists in ameliorating brain injury.

Public Health Relevance

Synaptic N-methyl-D-aspartic acid (NMDA) receptors (NMDARs), composed, in large part, of NR2A-containing NMDARs (NR2ARs), promote cell survival, whereas extrasynaptic NMDARs, NR2B-containing NMDARs (NR2BRs), induce cell death. This proposal investigates how HIV-1-infected mononuclear phagocytes (brain macrophages and microglia) activate neuronal extrasynaptic NR2BRs, leading to neuronal damage and ultimately neurocognitive dysfunction. By completion of the proposed studies we will not only provide new insights into the mechanisms underlying the neuropathogenesis of HIV-1 infection, but also furnish new target(s) for the development of potential therapies in the prevention and treatment of HIV-1 disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS063878-04
Application #
8214594
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2009-02-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
4
Fiscal Year
2012
Total Cost
$363,825
Indirect Cost
$118,825
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Zhou, Yan; Liu, Jianuo; Xiong, Huangui (2017) HIV-1 Glycoprotein 120 Enhancement of N-Methyl-D-Aspartate NMDA Receptor-Mediated Excitatory Postsynaptic Currents: Implications for HIV-1-Associated Neural Injury. J Neuroimmune Pharmacol 12:314-326
Wang, Yi; Li, Yuju; Zhao, Runze et al. (2017) Glutaminase C overexpression in the brain induces learning deficits, synaptic dysfunctions, and neuroinflammation in mice. Brain Behav Immun 66:135-145
Liu, Han; Liu, Jianuo; Xu, Enquan et al. (2017) Human immunodeficiency virus protein Tat induces oligodendrocyte injury by enhancing outward K+ current conducted by KV1.3. Neurobiol Dis 97:1-10
Zhou, Yan; Tang, Hongmei; Xiong, Huangui (2016) Chemokine CCL2 enhances NMDA receptor-mediated excitatory postsynaptic current in rat hippocampal slices-a potential mechanism for HIV-1-associated neuropathy? J Neuroimmune Pharmacol 11:306-15
Reiner, Benjamin; Wang, Wenwei; Liu, Jianuo et al. (2016) Platelet-activating factor attenuation of long-term potentiation in rat hippocampal slices via protein tyrosine kinase signaling. Neurosci Lett 615:83-7
Zhao, Jun; Liu, Jianuo; Xu, Enquan et al. (2016) dl-3-n-Butylphthalide attenuation of methamphetamine-induced neurotoxicity in SH-SY5Y neuroblastoma cells. Life Sci 165:16-20
Zhang, Jingdong; Liu, Jianuo; Fox, Howard S et al. (2013) N-methyl-D-aspartate receptor-mediated axonal injury in adult rat corpus callosum. J Neurosci Res 91:240-8
Yang, Jianming; Hu, Dehui; Xia, Jianxun et al. (2013) Enhancement of NMDA receptor-mediated excitatory postsynaptic currents by gp120-treated macrophages: implications for HIV-1-associated neuropathology. J Neuroimmune Pharmacol 8:921-33
Ton, Hoai; Xiong, Huangui (2013) Astrocyte Dysfunctions and HIV-1 Neurotoxicity. J AIDS Clin Res 4:255
Liu, J; Xu, C; Chen, L et al. (2012) Involvement of Kv1.3 and p38 MAPK signaling in HIV-1 glycoprotein 120-induced microglia neurotoxicity. Cell Death Dis 3:e254

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