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The Journal of Neuroscience, January 18, 2006, 26(3):981-990; doi:10.1523/JNEUROSCI.4617-05.2006

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Neurobiology of Disease
Human Immunodeficiency Virus (HIV)-Induced Neurotoxicity: Roles for the NMDA Receptor Subtypes

Lauren A. O'Donnell,¹ Arpita Agrawal,¹ Kelly L. Jordan-Sciutto,² Marc A. Dichter,¹ David R. Lynch,¹ and Dennis L. Kolson¹

¹Department of Neurology, School of Medicine, and ²Department of Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Neuronal damage in human immunodeficiency virus type 1 (HIV-1) infection in the brain is thought to occur at least in part through NMDA receptor (NMDAR) excitation initiated by soluble neurotoxins from HIV-infected brain macrophages. Furthermore, brain regions enriched in NMDAR-2A (NR2A) and NMDAR-2B (NR2B) subunits, such as the hippocampus, are particularly vulnerable. Using cultured rat hippocampal cells and HIV-1-infected human monocyte-derived macrophages (HIV/MDM), we examined the role of NR2A and NR2B in HIV/MDM-induced hippocampal neuronal death. We used the primary HIV-1 strain Jago derived from the CSF of an individual with HIV-associated dementia and that robustly replicates in MDM. We found the following: (1) hippocampal neuronal susceptibility to HIV/MDM excitotoxins varies according to the developmental expression patterns of NR2A and NR2B; (2) NMDAR activation by HIV/MDM results in neuronal calpain activation, which results in neuronal death; and (3) selective antagonists of homomeric NR2B/NR2B- and heteromeric NR2A/NR2B-containing NMDARs, as well as an inhibitor of calpain activity, afford neuroprotection against HIV/MDM. These studies establish a clear link between macrophage HIV infection, neuronal NR2A and NR2B activation, and calpain-mediated hippocampal neuronal death. They further suggest a dominant role for NR2A and NR2B in determining neuronal susceptibility in HIV-infected brain. Antagonists of NR2A and NR2B subunits as well as inhibitors of calpain activation offer attractive neuroprotective approaches against HIV in both developing and mature brain.

Key words: HIV-1; NMDA receptor; calpain; hippocampus; virus; neurotoxicity; macrophage

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Received Aug 25, 2005; revised December 1, 2005; accepted December 6, 2005.

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				V. R. Rao, A. R. Sas, E. A. Eugenin, N. B. Siddappa, H. Bimonte-Nelson, J. W. Berman, U. Ranga, W. R. Tyor, and V. R. Prasad HIV-1 Clade-Specific Differences in the Induction of Neuropathogenesis J. Neurosci., October 1, 2008; 28(40): 10010 - 10016. [Abstract] [Full Text] [PDF]

				Y. Liu, T. P. Wong, M. Aarts, A. Rooyakkers, L. Liu, T. W. Lai, D. C. Wu, J. Lu, M. Tymianski, A. M. Craig, et al. NMDA Receptor Subunits Have Differential Roles in Mediating Excitotoxic Neuronal Death Both In Vitro and In Vivo J. Neurosci., March 14, 2007; 27(11): 2846 - 2857. [Abstract] [Full Text] [PDF]

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