Skip to main content

Advertisement

SpringerLink
Log in

Differential Effects of Pharmacologic and Genetic Modulation of NMDA Receptor Activity on HIV/gp120-Induced Neuronal Damage in an In Vivo Mouse Model

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Chen HS, Lipton SA (1997) Mechanism of memantine block of NMDA-activated channels in rat retinal ganglion cells: uncompetitive antagonism. J Physiol 499:27–46

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chen HS, Pellegrini JW, Aggarwal SK, Lei SZ, Warach S, Jensen FE, Lipton SA (1992) Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptormediated neurotoxicity. J Neurosci 12:4427–4436

    CAS  PubMed  Google Scholar 

  • Ciabarra AM, Sullivan JM, Gahn LG, Pecht G, Heinemann S, Sevarino KA (1995) Cloning and characterization of chi-1: a developmentally regulated member of a novel class of the ionotropic glutamate receptor family. J Neurosci 15:6498–6508

    CAS  PubMed  Google Scholar 

  • Cull-Candy S, Brickley S, Farrant M (2001) NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol 11:327–335

    Article  CAS  PubMed  Google Scholar 

  • Das S, Sasaki YF, Rothe T, Premkumar LS, Takasu M, Crandall JE, Dikkes P, Conner DA, Rayudu PV, Cheung W, Chen HS, Lipton SA, Nakanishi N (1998) Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A. Nature 393:377–381

  • Dingledine R, Borges K, Bowie D, Traynelis SF (1999) The glutamate receptor ion channels. Pharmacol Rev 51:7–61

    CAS  PubMed  Google Scholar 

  • Everall IP, Heaton RK, Marcotte TD, Ellis RJ, McCutchan JA, Atkinson JH, Grant I, Mallory M, Masliah E (1999) Cortical synaptic density is reduced in mild to moderate human immunodeficiency virus neurocognitive disorder. Brain Pathol 9:209–217

  • Garden GA, Budd SL, Tsai E, Hanson L, Kaul M, D'Emilia DM, Friedlander RM, Yuan J, Masliah E, Lipton SA (2002) Caspase cascades in human immunodeficiency virus-associated neurodegeneration. J Neurosci 22:4015–4024

    CAS  PubMed  Google Scholar 

  • Gorantla S, Liu J, Sneller H, Dou H, Holguin A, Smith L, Ikezu T, Volsky DJ, Poluektova L, Gendelman HE (2007) Copolymer-1 induces adaptive immune anti-inflammatory glial and neuroprotective responses in a murine model of HIV-1 encephalitis. J Immunol 179:4345–4356

    Article  CAS  PubMed  Google Scholar 

  • Hardingham GE, Bading H (2010) Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 11(10):682–696

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hollmann M, Heinemann S (1994) Cloned glutamate receptors. Annu Rev Neurosci 17:31–108

    Article  CAS  PubMed  Google Scholar 

  • Kang YJ, Digicaylioglu M, Russo R, Kaul M, Achim CL, Fletcher L, Masliah E, Lipton SA (2010) Erythropoietin plus insulin-like growth factor-I protects against neuronal damage in a murine model of human immunodeficiency virus-associated neurocognitive disorders. Ann Neurol 68:342–352

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kaul M, Garden GA, Lipton SA (2001) Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410:988–994

    Article  CAS  PubMed  Google Scholar 

  • Kehoe LA, Bellone C, De Roo M, Zandueta A, Dey PN, Perez-Otano I, Muller D (2014) GluN3A promotes dendritic spine pruning and destabilization during postnatal development. J Neurosci 34(28):9213–9221

    Article  PubMed  Google Scholar 

  • Kolson DL (2002) Neuropathogenesis of central nervous system HIV-1 infection. Clin Lab Med 22:703–717

    Article  PubMed  Google Scholar 

  • Lipton SA (2006) Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nature Rev Drug Disc 5:160–170

    Article  CAS  Google Scholar 

  • Lipton SA, Gendelman HE (1995) Dementia associated with the acquired immunodeficiency syndrome. N Engl J Med 332:934–940

    Article  CAS  PubMed  Google Scholar 

  • Lipton SA, Rosenberg PA (1994) Mechanisms of disease: excitatory amino acids as a final common pathway in neurologic disorders. N Engl J Med 330:613–622

    Article  CAS  PubMed  Google Scholar 

  • Marco S, Giralt A, Petrovic MM, Pouladi MA, Martinez-Turrillas R, Martinez-Hernandez J, Kaltenbach LS, Torres-Peraza J, Graham RK, Watanabe M, Lujan R, Nakanishi N, Lipton SA, Lo DC, Hayden MR, Alberch J, Wesseling JF, Perez-Otano I (2013) Suppressing aberrant GluN3A expression rescues synaptic and behavioral impairments in Huntington’s disease models. Nat Med 19(8):1030–1038

  • Martínez-Turrillas R, Puerta E, Chowdhury D, Marco S, Watanabe M, Aguirre N, Pérez-Otaño I (2012) The NMDA receptor subunit GluN3A protects against 3-nitroproprionic-induced striatal lesions via inhibition of calpain activation. Neurobiol Dis 48:290–298

    Article  PubMed  Google Scholar 

  • Masliah E, Mallory M, Hansen L, DeTeresa R, Alford M, Terry R (1994) Synaptic and neuritic alterations during the progression of Alzheimer’s disease. Neurosci Lett 174:67–72

    Article  CAS  PubMed  Google Scholar 

  • Mayford M, Bach ME, Huang YY, Wang L, Hawkins RD, Kandel ER (1996) Control of memory formation through regulated expression of a CaMKII transgene. Science 274:1678–1683

    Article  CAS  PubMed  Google Scholar 

  • McArthur JC (2004) HIV dementia: an evolving disease. J Neuroimmunol 157:3–10

    Article  CAS  PubMed  Google Scholar 

  • Mocchetti I, Bachis A, Masliah E (2008) Chemokine receptors and neurotrophic factors: potential therapy against aids dementia? J Neurosci Res 86:243–255

    Article  CAS  PubMed  Google Scholar 

  • Nakanishi N, Tu S, Shin Y, Cui J, Kurokawa T, Zhang D, Chen HS, Tong G, Lipton SA (2009) Neuroprotection by the NR3A subunit of the NMDA receptor. J Neurosci 29:5260–5265

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Okamoto S-I, Pouladi M, Talantova M, Yao D, Xia P, Ehrnhoefer DE, Zaidi R, Clemente A, Kaul M, Graham RK, Zhang D, Vincent Chen HS, Tong G, Hayden MR, Lipton SA (2009) Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nature Med 15:1407–1413

  • Pérez-Otaño I, Schulteis CT, Contractor A, Lipton SA, Trimmer JS, Sucher NJ, Heinemann SF (2001) Assembly with the NR1 subunit is required for surface expression of NR3A-containing NMDA receptors. J Neurosci 21:1228–1237

  • Potula R, Poluektova L, Knipe B, Chrastil J, Heilman D, Dou H, Takikawa O, Munn DH, Gendelman HE, Persidsky Y (2005) Inhibition of indoleamine 2,3-dioxygenase (IDO) enhances elimination of virus-infected macrophages in an animal model of HIV-1 encephalitis. Blood 106:2382–2390

  • Sasaki YF, Rothe T, Premkumar LS, Das S, Cui J, Talantova MV, Wong HK, Gong X, Chan SF, Zhang D, Nakanishi N, Sucher NJ, Lipton SA (2002) Characterization and comparison of the NR3A subunit of the NMDA receptor in recombinant systems and primary cerebrocortical neurons. J Neurophysiol 87:2052–2063

  • Schifitto G, Navia GA, Yiannoustsos CT, Marra CM, Chang L, Ernst T, Jarvik JG, Miller EN, Singer EJ, Ellis RJ, Kolson DL, Nath A, Berger J, Shriver SL, Millar LL, Colquhoun D, Lenkinski R, Gonzalez RG, Lipton SA, Adult AIDS Clinical Trial Group (ACTG) 301 and 700 Teams, HIV MRS Consortium (2007) Memantine and HIV-associated cognitive impairment: a neuropsychological and proton magnetic resonance spectroscopy study. AIDS 21:1877–1886

  • Sucher NJ, Akbarian S, Chi CL, Leclerc CL, Awobuluyi M, Deitcher DL, Wu MK, Yuan JP, Jones EG, Lipton SA (1995) Developmental and regional expression pattern of a novel NMDA receptor-like subunit (NMDARL) in the rodent brain. J Neurosci 15:6509–6520

    CAS  PubMed  Google Scholar 

  • Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar MW, Okamoto S, Dziewczapolski G, Nakamura T, Cao G, Pratt AE, Kang YJ, Tu S, Molokanova E, McKercher SR, Hires SA, Sason H, Stouffer DG, Buczynski MW, Solomon JP, Michael S, Powers ET, Kelly JW, Roberts A, Tong G, Fang-Newmeyer T, Parker J, Holland EA, Zhang D, Nakanishi N, Chen HS et al. (2013) Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci U S A 110:E2518–2527

  • Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 40:572–580

    Article  Google Scholar 

  • Toggas SM, Masliah E, Rockenstein EM, Rall GF, Abraham CR, Mucke L (1994) Central nervous system damage produced by expression of the HIV-1 coat protein gp120 in transgenic mice. Nature 367:188–193

    Article  CAS  PubMed  Google Scholar 

  • Toggas SM, Masliah E, Mucke L (1996) Prevention of HIV-1 gp120-induced neuronal damage in the central nervous system of transgenic mice by the NMDA receptor antagonist memantine. Brain Res 706:303–307

    Article  CAS  PubMed  Google Scholar 

  • Tong G, Takahashi H, Tu S, Shin Y, Talantova M, Zago W, Xia P, Nie Z, Goetz T, Zhang D, Lipton SA, Nakanishi N (2008) Modulation of NMDA receptor properties and synaptic transmission by the NR3A subunit in mouse hippocampal and cerebrocortical neurons. J Neurophysiol 99:122–132

  • Wang Y, Eu J, Washburn M, Gong T, Chen HS, James WL, Lipton SA, Stamler JS, Went GT, Porter S (2006) The pharmacology of aminoadamantane nitrates. Curr Alzheimer Res 3:201–204

    Article  PubMed  Google Scholar 

  • Wong H-K, Liu XB, Matos MF, Chan SF, Perez-Otano I, Boysen M, Cui J, Nakanishi N, Trimmer JS, Jones EG, Lipton SA, Sucher NJ (2002) Temporal and anatomical expression of NMDA receptor subunit NR3A in the mammalian brain. J Comp Neurol 450:303–317

  • Xia P, Chen H-SV, Zhang D, Lipton SA (2010) Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses. J Neurosci 30:11246–11250

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank James Parker for graphic assistance. This work was supported in part by NIH grants P01 HD29587, P30 NS076411, R21 NS083415, and R01 EY09024 to S.A.L. Additional support was provided by a Distinguished Investigator Award from the Brain & Behavior Research Foundation to S.A.L.

Conflict of interest

S.A.L. is the named inventor on worldwide patents for memantine (Namenda®) and NitroMemantine for the treatment of neurodegenerative diseases. Following Harvard University guidelines, he participates in a royalty sharing agreement with his former institution Harvard Medical School/Boston Children’s Hospital for the licensing of the memantine patents to Forest Laboratories/Actavis. He is also a Scientific Co-Founder of Adamas Pharmaceuticals, Inc., which has agreements with Forest Laboratories/Actavis for co-developing long-lasting formulations of memantine. The authors declare that they have no other competing interests.

Author information

Authors and Affiliations

  1. Center for Neuroscience and Aging Research, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA

    Nobuki Nakanishi, Yeon-Joo Kang, Shichun Tu, Scott R. McKercher & Stuart A. Lipton

  2. Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, 92093, USA

    Eliezer Masliah & Stuart A. Lipton

  3. Present Address: Scintillon Institute, 6868 Nancy Ridge Drive, San Diego, CA, 92121, USA

    Nobuki Nakanishi, Scott R. McKercher & Stuart A. Lipton

Authors
  1. Nobuki Nakanishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yeon-Joo Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shichun Tu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Scott R. McKercher
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eliezer Masliah
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Stuart A. Lipton
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stuart A. Lipton.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nakanishi, N., Kang, YJ., Tu, S. et al. Differential Effects of Pharmacologic and Genetic Modulation of NMDA Receptor Activity on HIV/gp120-Induced Neuronal Damage in an In Vivo Mouse Model. J Mol Neurosci 58, 59–65 (2016). https://doi.org/10.1007/s12031-015-0651-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-015-0651-1

Keywords

Search

Navigation