title: Differential Effects of Pharmacologic and Genetic Modulation of NMDA Receptor Activity on HIV/gp120-Induced Neuronal Damage in an In Vivo Mouse Model.
abstract: HIV-associated neurocognitive disorder (HAND) consists of motor and cognitive dysfunction in a relatively large percentage of patients with AIDS. Prior work has suggested that at least part of the neuronal and synaptic damage observed in HAND may occur due to excessive stimulation of NMDA-type glutamate receptors (NMDARs). Here, we compared pharmacological and genetic manipulation of NMDAR activity using an improved derivative of the NMDAR antagonist memantine, termed NitroMemantine, and the modulatory NMDAR subunit GluN3A in the HIV/gp120 transgenic (tg) mouse model of HAND. Interestingly, we found that while both NitroMemantine and GluN3A have been shown to inhibit NMDAR activity, NitroMemantine protected synapses in gp120-tg mice, but overexpression of GluN3A augmented the damage. Given recent findings in the field, one explanation for this apparently paradoxical result is the location of the NMDARs primarily affected, with NitroMemantine inhibiting predominantly extrasynaptic pathologically activated NMDARs, but GluN3A disrupting normal NMDAR-mediated neuroprotective activity via inhibition of synaptic NMDARs.
authors.affiliation: Center for Neuroscience and Aging Research, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.|Present Address: Scintillon Institute, 6868 Nancy Ridge Drive, San Diego, CA, 92121, USA.
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nakanishi
authors.affiliation: Center for Neuroscience and Aging Research, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
authors.forename: Yeon-Joo
authors.initials: YJ
authors.lastname: Kang
authors.affiliation: Center for Neuroscience and Aging Research, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
authors.forename: Shichun
authors.initials: S
authors.lastname: Tu
authors.affiliation: Center for Neuroscience and Aging Research, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.|Present Address: Scintillon Institute, 6868 Nancy Ridge Drive, San Diego, CA, 92121, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: McKercher
authors.affiliation: Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
authors.affiliation: Center for Neuroscience and Aging Research, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA. slipton@ucsd.edu.|Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA. slipton@ucsd.edu.|Present Address: Scintillon Institute, 6868 Nancy Ridge Drive, San Diego, CA, 92121, USA. slipton@ucsd.edu.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
mesh_terms: D015526:AIDS Dementia Complex / Q000188:drug therapy / Q000209:etiology / Q000628:therapy*; D000818:Animals; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D015316:Genetic Therapy; D015699:HIV Envelope Protein gp120 / Q000633:toxicity; D008559:Memantine / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; C584082:GluN3A protein, mouse; D015699:HIV Envelope Protein gp120; D016194:Receptors, N-Methyl-D-Aspartate; D008559:Memantine
keywords: AIDS; GluN3A; HIV-associated neurocognitive disorder (HAND); Memantine; NMDA-type glutamate receptors; NitroMemantine; gp120