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 #
5R01NS063878-05
Application #
8415818
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2009-02-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2013
Total Cost
$351,091
Indirect Cost
$114,666
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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Zhou, Yan; Tang, Hongmei; Liu, Jianuo et al. (2011) Chemokine CCL2 modulation of neuronal excitability and synaptic transmission in rat hippocampal slices. J Neurochem 116:406-14
Jing, Tao; Wu, Li; Borgmann, Kathleen et al. (2010) Soluble factors from IL-1*-stimulated astrocytes activate NR1a/NR2B receptors: implications for HIV-1-induced neurodegeneration. Biochem Biophys Res Commun 402:241-6