Advertisement

Scaling Synapses in the Presence of HIV

  • Matthew V. Green
  • Jonathan D. Raybuck
  • Xinwen Zhang
  • Mariah M. Wu
  • Stanley A. Thayer
Original Paper
  • 137 Downloads

Abstract

A defining feature of HIV-associated neurocognitive disorder (HAND) is the loss of excitatory synaptic connections. Synaptic changes that occur during exposure to HIV appear to result, in part, from a homeostatic scaling response. Here we discuss the mechanisms of these changes from the perspective that they might be part of a coping mechanism that reduces synapses to prevent excitotoxicity. In transgenic animals expressing the HIV proteins Tat or gp120, the loss of synaptic markers precedes changes in neuronal number. In vitro studies have shown that HIV-induced synapse loss and cell death are mediated by distinct mechanisms. Both in vitro and animal studies suggest that HIV-induced synaptic scaling engages new mechanisms that suppress network connectivity and that these processes might be amenable to therapeutic intervention. Indeed, pharmacological reversal of synapse loss induced by HIV Tat restores cognitive function. In summary, studies indicate that there are temporal, mechanistic and pharmacological features of HIV-induced synapse loss that are consistent with homeostatic plasticity. The increasingly well delineated signaling mechanisms that regulate synaptic scaling may reveal pharmacological targets suitable for normalizing synaptic function in chronic neuroinflammatory states such as HAND.

Keywords

HIV-1 Homeostatic plasticity NMDA receptor Synaptic scaling HIV-associated neurocognitive disorder 

Notes

Acknowledgements

This work was supported by the National Institute on Drug Abuse—National Institutes of Health Grant DA07304.

Compliance with Ethical Standards

Conflict of interest

The authors declare they have no competing interests.

References

  1. 1.
    Ellis R, Langford D, Masliah E (2007) HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci 8:33–44PubMedCrossRefGoogle Scholar
  2. 2.
    Ellis RJ, Calero P, Stockin MD (2009) HIV infection and the central nervous system: a primer. Neuropsychol Rev 19:144–151PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    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 (HNRC Group. HIV Neurobehavioral Research Center)PubMedCrossRefGoogle Scholar
  4. 4.
    Ru W, Tang SJ (2017) HIV-associated synaptic degeneration. Mol Brain 10:40PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Saylor D, Dickens AM, Sacktor N, Haughey N, Slusher B, Pletnikov M, Mankowski JL, Brown A, Volsky DJ, McArthur JC (2016) HIV-associated neurocognitive disorder - pathogenesis and prospects for treatment. Nat Rev Neurol 12:234–248PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Kaul M, Garden GA, Lipton SA (2001) Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410:988–994PubMedCrossRefGoogle Scholar
  7. 7.
    Turrigiano GG (2008) The self-tuning neuron: synaptic scaling of excitatory synapses. Cell 135:422–435PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Bellizzi MJ, Lu SM, Gelbard HA (2006) Protecting the synapse: evidence for a rational strategy to treat HIV-1 associated neurologic disease. J Neuroimmune Pharmacol 1:20–31PubMedCrossRefGoogle Scholar
  9. 9.
    Mandolesi G, Gentile A, Musella A, Fresegna D, De Vito F, Bullitta S, Sepman H, Marfia GA, Centonze D (2015) Synaptopathy connects inflammation and neurodegeneration in multiple sclerosis. Nat Rev Neurol 11:711–724PubMedCrossRefGoogle Scholar
  10. 10.
    Rao JS, Kellom M, Kim HW, Rapoport SI, Reese EA (2012) Neuroinflammation and synaptic loss. Neurochem Res 37:903–910PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ, Stevens B (2016) Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352:712–716PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Bandaru VV, McArthur JC, Sacktor N, Cutler RG, Knapp EL, Mattson MP, Haughey NJ (2007) Associative and predictive biomarkers of dementia in HIV-1-infected patients. Neurology 68:1481–1487PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Yuan L, Qiao L, Wei F, Yin J, Liu L, Ji Y, Smith D, Li N, Chen D (2013) Cytokines in CSF correlate with HIV-associated neurocognitive disorders in the post-HAART era in China. J Neurovirol 19:144–149PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Beckhauser TF, Francis-Oliveira J, De Pasquale R (2016) Reactive oxygen species: physiological and physiopathological effects on synaptic plasticity. J Exp Neurosci 10:23–48PubMedPubMedCentralGoogle Scholar
  15. 15.
    Louboutin JP, Agrawal L, Reyes BA, van Bockstaele EJ, Strayer DS (2012) Gene delivery of antioxidant enzymes inhibits human immunodeficiency virus type 1 gp120-induced expression of caspases. Neurosci 214:68–77CrossRefGoogle Scholar
  16. 16.
    Hui L, Chen X, Bhatt D, Geiger NH, Rosenberger TA, Haughey NJ, Masino SA, Geiger JD (2012) Ketone bodies protection against HIV-1 Tat-induced neurotoxicity. J Neurochem 122:382–391PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Akay C, Cooper M, Odeleye A, Jensen BK, White MG, Vassoler F, Gannon PJ, Mankowski J, Dorsey JL, Buch AM, Cross SA, Cook DR, Pena MM, Andersen ES, Christofidou-Solomidou M, Lindl KA, Zink MC, Clements J, Pierce RC, Kolson DL, Jordan-Sciutto KL (2014) Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system. J Neurovirol 20:39–53PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Agrawal L, Louboutin JP, Reyes BA, Van Bockstaele EJ, Strayer DS (2012) HIV-1 Tat neurotoxicity: a model of acute and chronic exposure, and neuroprotection by gene delivery of antioxidant enzymes. Neurobiol Dis 45:657–670PubMedCrossRefGoogle Scholar
  19. 19.
    Viviani B, Corsini E, Binaglia M, Galli CL, Marinovich M (2001) Reactive oxygen species generated by glia are responsible for neuron death induced by human immunodeficiency virus-glycoprotein 120 in vitro. Neurosci 107:51–58CrossRefGoogle Scholar
  20. 20.
    Kim SH, Smith AJ, Tan J, Shytle RD, Giunta B (2015) MSM ameliorates HIV-1 Tat induced neuronal oxidative stress via rebalance of the glutathione cycle. Am J Transl Res 7:328–338PubMedPubMedCentralGoogle Scholar
  21. 21.
    Kim HJ, Martemyanov KA, Thayer SA (2008) Human immunodeficiency virus protein Tat induces synapse loss via a reversible process that is distinct from cell death. J Neurosci 28:12604–12613PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Fitting S, Ignatowska-Jankowska BM, Bull C, Skoff RP, Lichtman AH, Wise LE, Fox MA, Su J, Medina AE, Krahe TE, Knapp PE, Guido W, Hauser KF (2012) Synaptic dysfunction in the hippocampus accompanies learning and memory deficits in human immunodeficiency virus type-1 tat transgenic mice. Biol Psychiatry 73:443–453PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    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 367:188–193PubMedCrossRefGoogle Scholar
  24. 24.
    Kim HJ, Shin AH, Thayer SA (2011) Activation of cannabinoid type 2 receptors inhibits HIV-1 envelope glycoprotein gp120-induced synapse loss. Mol Pharmacol 80:357–366PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Festa L, Gutoskey CJ, Graziano A, Waterhouse BD, Meucci O (2015) Induction of interleukin-1β by human immunodeficiency virus-1 viral proteins leads to increased levels of neuronal ferritin heavy chain, synaptic injury, and deficits in flexible attention. J Neurosci 35:10550–10561PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Bertrand SJ, Aksenova MV, Mactutus CF, Booze RM (2013) HIV-1 Tat protein variants: critical role for the cysteine region in synaptodendritic injury. Exp Neurol 248:228–235PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Bertrand SJ, Mactutus CF, Aksenova MV, Espensen-Sturges TD, Booze RM (2014) Synaptodendritic recovery following HIV Tat exposure: neurorestoration by phytoestrogens. J Neurochem 128:140–151PubMedCrossRefGoogle Scholar
  28. 28.
    Hahn YK, Podhaizer EM, Farris SP, Miles MF, Hauser KF, Knapp PE (2015) Effects of chronic HIV-1 Tat exposure in the CNS: heightened vulnerability of males versus females to changes in cell numbers, synaptic integrity, and behavior. Brain Struct Funct 220:605–623PubMedCrossRefGoogle Scholar
  29. 29.
    Michaud J, Fajardo R, Charron G, Sauvageau A, Berrada F, Ramla D, Dilhuydy H, Robitaille Y, Kessous-Elbaz A (2001) Neuropathology of NFHgp160 transgenic mice expressing HIV-1 env protein in neurons. J Neuropathol Exp Neurol 60:574–587PubMedCrossRefGoogle Scholar
  30. 30.
    Fitting S, Ignatowska-Jankowska BM, Bull C, Skoff RP, Lichtman AH, Wise LE, Fox MA, Su J, Medina AE, Krahe TE, Knapp PE, Guido W, Hauser KF (2013) Synaptic dysfunction in the hippocampus accompanies learning and memory deficits in human immunodeficiency virus type-1 Tat transgenic mice. Biol Psychiatry 73:443–453PubMedCrossRefGoogle Scholar
  31. 31.
    Shin AH, Kim HJ, Thayer SA (2012) Subtype selective NMDA receptor antagonists induce recovery of synapses lost following exposure to HIV-1 Tat. Br J Pharmacol 166:1002–1017PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Raybuck JD, Hargus NJ, Thayer SA (2017) A GluN2B-Selective NMDAR antagonist reverses synapse loss and cognitive impairment produced by the HIV-1 protein Tat. J Neurosci 37:7837–7847PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Hu XT (2015) HIV-1 Tat-mediated calcium dysregulation and neuronal dysfunction in vulnerable brain regions. Curr Drug Targets 17(1):4–14CrossRefGoogle Scholar
  34. 34.
    Krogh KA, Wydeven N, Wickman K, Thayer SA (2014) HIV-1 protein Tat produces biphasic changes in NMDA-evoked increases in intracellular Ca concentration via activation of Src kinase and nitric oxide signaling pathways. J Neurochem 130:642–656PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Haughey NJ, Nath A, Mattson MP, Slevin JT, Geiger JD (2001) HIV-1 Tat through phosphorylation of NMDA receptors potentiates glutamate excitotoxicity. J Neurochem 78:457–467PubMedCrossRefGoogle Scholar
  36. 36.
    Viviani B, Gardoni F, Bartesaghi S, Corsini E, Facchi A, Galli CL, Di Luca M, Marinovich M (2006) Interleukin-1β released by gp120 drives neural death through tyrosine phosphorylation and trafficking of NMDA receptors. J Biol Chem 281:30212–30222PubMedCrossRefGoogle Scholar
  37. 37.
    Jara JH, Singh BB, Floden AM, Combs CK (2007) Tumor necrosis factor alpha stimulates NMDA receptor activity in mouse cortical neurons resulting in ERK-dependent death. J Neurochem 100:1407–1420PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Prendergast MA, Rogers DT, Mulholland PJ, Littleton JM, Wilkins LH, Self RL, Nath A (2002) Neurotoxic effects of the human immunodeficiency virus type-1 transcription factor Tat require function of a polyamine sensitive-site on the N-methyl-D-aspartate receptor. Brain Res 954:300–307PubMedCrossRefGoogle Scholar
  39. 39.
    King JE, Eugenin EA, Hazleton JE, Morgello S, Berman JW (2010) Mechanisms of HIV-tat-induced phosphorylation of N-methyl-D-aspartate receptor subunit 2A in human primary neurons: implications for neuroAIDS pathogenesis. Am J Pathol 176:2819–2830PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Xu H, Bae M, Tovar-y-Romo LB, Patel N, Bandaru VV, Pomerantz D, Steiner JP, Haughey NJ The human immunodeficiency virus coat protein gp120 promotes forward trafficking and surface clustering of NMDA receptors in membrane microdomains. J Neurosci 31:17074–17090Google Scholar
  41. 41.
    Mishra A, Kim HJ, Shin AH, Thayer SA (2012) Synapse loss induced by interleukin-1beta requires pre- and post-synaptic mechanisms. J Neuroimmune Pharmacol 7:571–578PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Zhang X, Thayer SA (2018) Monoacylglycerol lipase inhibitor JZL184 prevents HIV-1 gp120-induced synapse loss by altering endocannabinoid signaling. Neuropharmacol 128:269–281CrossRefGoogle Scholar
  43. 43.
    Green MV, Thayer SA (2016) NMDARs adapt to neurotoxic HIV protein Tat downstream of a GluN2A-ubiquitin ligase signaling pathway. J Neurosci 36:12640–12649PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Ru W, Tang SJ (2015) HIV-1 gp120Bal down-regulates Phosphorylated NMDA receptor subunit 1 in cortical neurons via activation of glutamate and chemokine receptors. J Neuroimmune Pharmacol 11(1):182–191PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Masliah E, Roberts ES, Langford D, Everall I, Crews L, Adame A, Rockenstein E, Fox HS (2004) Patterns of gene dysregulation in the frontal cortex of patients with HIV encephalitis. J Neuroimmunol 157:163–175PubMedCrossRefGoogle Scholar
  46. 46.
    Shipton OA, Paulsen O (2014) GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity. Philos Trans R Soc Lond B 369:20130163CrossRefGoogle Scholar
  47. 47.
    Liu Y, Wong TP, Aarts M, Rooyakkers A, Liu L, Lai TW, Wu DC, Lu J, Tymianski M, Craig AM, Wang YT (2007) NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J Neurosci 27:2846–2857PubMedCrossRefGoogle Scholar
  48. 48.
    Chen M, Lu TJ, Chen XJ, Zhou Y, Chen Q, Feng XY, Xu L, Duan WH, Xiong ZQ (2008) Differential roles of NMDA receptor subtypes in ischemic neuronal cell death and ischemic tolerance. Stroke 39:3042–3048PubMedCrossRefGoogle Scholar
  49. 49.
    Hardingham GE, Fukunaga Y, Bading H (2002) Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci 5:405–414PubMedCrossRefGoogle Scholar
  50. 50.
    Hardingham GE, Bading H (2010) Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 11(10):682PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Rozzi SJ, Avdoshina V, Fields JA, Trejo M, Ton HT, Ahern GP, Mocchetti I (2017) Human Immunodeficiency Virus Promotes Mitochondrial Toxicity. Neurotox ResGoogle Scholar
  52. 52.
    Fitting S, Knapp PE, Zou S, Marks WD, Bowers MS, Akbarali HI, Hauser KF (2014) Interactive HIV-1 Tat and morphine-induced synaptodendritic injury is triggered through focal disruptions in Na+ influx, mitochondrial instability, and Ca2+ overload. J Neurosci 34:12850–12864PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Haughey NJ, Mattson TP (2002) Calcium dysregulation and neuronal apoptosis by the HIV-1 proteins tat and gp120. JAIDS 31:S55-S61Google Scholar
  54. 54.
    Malik S, Eugenin EA (2017) Role of Connexin and Pannexin containing channels in HIV infection and NeuroAIDS. Neurosci Lett.  https://doi.org/10.1016/j.neulet.2017.09.005 PubMedGoogle Scholar
  55. 55.
    Weilinger NL, Lohman AW, Rakai BD, Ma EM, Bialecki J, Maslieieva V, Rilea T, Bandet MV, Ikuta NT, Scott L, Colicos MA, Teskey GC, Winship IR, Thompson RJ (2016) Metabotropic NMDA receptor signaling couples Src family kinases to pannexin-1 during excitotoxicity. Nat Neurosci 19:432–442PubMedCrossRefGoogle Scholar
  56. 56.
    Hu R, Chen J, Lujan B, Lei R, Zhang M, Wang Z, Liao M, Li Z, Wan Y, Liu F, Feng H, Wan Q (2016) Glycine triggers a non-ionotropic activity of GluN2A-containing NMDA receptors to confer neuroprotection. Sci Rep 6:34459PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Nabavi S, Kessels HW, Alfonso S, Aow J, Fox R, Malinow R (2013) Metabotropic NMDA receptor function is required for NMDA receptor-dependent long-term depression. Proc Natl Acad Sci USA 110:4027–4032PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Gelman BB, Nguyen TP (2010) Synaptic proteins linked to HIV-1 infection and immunoproteasome induction: proteomic analysis of human synaptosomes. J Neuroimmune Pharmacol 5:92–102PubMedCrossRefGoogle Scholar
  59. 59.
    Shin AH, Thayer SA (2013) Human immunodeficiency virus-1 protein Tat induces excitotoxic loss of presynaptic terminals in hippocampal cultures. Mol Cell Neurosci 54:22–29PubMedCrossRefGoogle Scholar
  60. 60.
    Hargus NJ, Thayer SA (2013) Human immunodeficiency virus-1 Tat protein increases the number of inhibitory synapses between hippocampal neurons in culture. J Neurosci 33:17908–17920PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Malenka RC, Bear MF (2004) LTP and LTD: an embarrassment of riches. Neuron 44:5–21PubMedCrossRefGoogle Scholar
  62. 62.
    Strack S, Colbran RJ (1998) Autophosphorylation-dependent targeting of calcium/ calmodulin-dependent protein kinase II by the NR2B subunit of the N-methyl-D-aspartate receptor. J Biol Chem 273:20689–20692PubMedCrossRefGoogle Scholar
  63. 63.
    Ding JD, Kennedy MB, Weinberg RJ (2013) Subcellular organization of camkii in rat hippocampal pyramidal neurons. J Comp Neurol 521:3570–3583PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Swulius MT, Waxham MN (2008) Ca2+/calmodulin-dependent protein kinases. Cell Mol Life Sci 65:2637–2657PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Lisman J, Schulman H, Cline H (2002) The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci 3:175–190PubMedCrossRefGoogle Scholar
  66. 66.
    Hook SS, Means AR (2001) Ca2+/CaM-dependent kinases: from activation to function. Annu Rev Pharmacol Toxicol 41:471–505PubMedCrossRefGoogle Scholar
  67. 67.
    Tian L, Stefanidakis M, Ning L, Van Lint P, Nyman-Huttunen H, Libert C, Itohara S, Mishina M, Rauvala H, Gahmberg CG (2007) Activation of NMDA receptors promotes dendritic spine development through MMP-mediated ICAM-5 cleavage. J Cell Biol 178:687–700PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Louboutin JP, Reyes BA, Agrawal L, Van Bockstaele EJ, Strayer DS (2011) HIV-1 gp120 upregulates matrix metalloproteinases and their inhibitors in a rat model of HIV encephalopathy. Eur J Neurosci 34:2015–2023PubMedCrossRefGoogle Scholar
  69. 69.
    Sanderson JL, Gorski JA, Dell’Acqua ML (2016) NMDA receptor-dependent LTD requires transient synaptic incorporation of Ca2+-permeable AMPARs mediated by AKAP150-anchored PKA and calcineurin. Neuron 89:1000–1015PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Lai TW, Zhang S, Wang YT (2014) Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog Neurobiol 115:157–188PubMedCrossRefGoogle Scholar
  71. 71.
    Rutherford LC, Nelson SB, Turrigiano GG (1998) BDNF has opposite effects on the quantal amplitude of pyramidal neuron and interneuron excitatory synapses. Neuron 21:521–530PubMedCrossRefGoogle Scholar
  72. 72.
    Desai NS, Rutherford LC, Turrigiano GG (1999) BDNF regulates the intrinsic excitability of cortical neurons. Learn Mem 6:284–291PubMedPubMedCentralGoogle Scholar
  73. 73.
    Bachis A, Avdoshina V, Zecca L, Parsadanian M, Mocchetti I (2012) Human immunodeficiency virus type 1 alters brain-derived neurotrophic factor processing in neurons. J Neurosci 32:9477–9484PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Nosheny RL, Bachis A, Acquas E, Mocchetti I (2004) Human immunodeficiency virus type 1 glycoprotein gp120 reduces the levels of brain-derived neurotrophic factor in vivo: potential implication for neuronal cell death. Eur J Neurosci 20:2857–2864PubMedCrossRefGoogle Scholar
  75. 75.
    Rahimian P, He JJ (2016) HIV-1 Tat-shortened neurite outgrowth through regulation of microRNA-132 and its target gene expression. J Neuroinflammation 13:247PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Albrecht D, Garcia L, Cartier L, Kettlun AM, Vergara C, Collados L, Valenzuela MA (2006) Trophic factors in cerebrospinal fluid and spinal cord of patients with tropical spastic paraparesis, HIV, and Creutzfeldt-Jakob disease. AIDS Res Hum Retrovir 22:248–254PubMedCrossRefGoogle Scholar
  77. 77.
    Meeker RB, Poulton W, Markovic-Plese S, Hall C, Robertson K (2011) Protein changes in CSF of HIV-infected patients: evidence for loss of neuroprotection. J Neurovirol 17:258–273PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Banerjee S, Liao L, Russo R, Nakamura T, McKercher SR, Okamoto S, Haun F, Nikzad R, Zaidi R, Holland E, Eroshkin A, Yates JR 3rd, Lipton SA (2012) Isobaric tagging-based quantification by mass spectrometry of differentially regulated proteins in synaptosomes of HIV/gp120 transgenic mice: implications for HIV-associated neurodegeneration. Exp Neurol 236:298–306PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Raja R, Ronsard L, Lata S, Trivedi S, Banerjea AC (2017) HIV-1 Tat potently stabilises Mdm2 and enhances viral replication. Biochem J 474:2449–2464PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Perez-Otano I, Ehlers MD (2005) Homeostatic plasticity and NMDA receptor trafficking. Trends Neurosci 28:229–238PubMedCrossRefGoogle Scholar
  81. 81.
    Nguyen TP, Soukup VM, Gelman BB (2010) Persistent hijacking of brain proteasomes in HIV-associated dementia. Am J Pathol 176:893–902PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Colledge M, Snyder EM, Crozier RA, Soderling JA, Jin Y, Langeberg LK, Lu H, Bear MF, Scott JD (2003) Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression. Neuron 40:595–607PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Fuchs SY, Adler V, Buschmann T, Wu X, Ronai Z (1998) Mdm2 association with p53 targets its ubiquitination. Oncogene 17:2543–2547PubMedCrossRefGoogle Scholar
  84. 84.
    Aprea S, Del Valle L, Mameli G, Sawaya BE, Khalili K, Peruzzi F (2006) Tubulin-mediated binding of human immunodeficiency virus-1 Tat to the cytoskeleton causes proteasomal-dependent degradation of microtubule-associated protein 2 and neuronal damage. J Neurosci 26:4054–4062PubMedCrossRefGoogle Scholar
  85. 85.
    Rechsteiner M, Rogers SW (1996) PEST sequences and regulation by proteolysis. Trends Biochem Sci 21:267–271PubMedCrossRefGoogle Scholar
  86. 86.
    Levy JM, Chen X, Reese TS, Nicoll RA (2015) Synaptic consolidation normalizes AMPAR quantal size following MAGUK loss. Neuron 87:534–548PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Bissel SJ, Wang G, Ghosh M, Reinhart TA, Capuano S 3rd, Cole KS, Murphey-Corb M, Piatak M Jr, Lifson JD, Wiley CA (2002) Macrophages relate presynaptic and postsynaptic damage in simian immunodeficiency virus encephalitis. Am J Pathol 160:3 927–941CrossRefGoogle Scholar
  88. 88.
    Kovalevich J, Langford D (2012) Neuronal toxicity in HIV CNS disease. Future Virol 7:687–698PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Lam S, Wiercinska E, Teunisse AF, Lodder K, ten Dijke P, Jochemsen AG (2014) Wild-type p53 inhibits pro-invasive properties of TGF-beta3 in breast cancer, in part through regulation of EPHB2, a new TGF-beta target gene. Breast Cancer Res Treat 148:7–18PubMedCrossRefGoogle Scholar
  90. 90.
    Yuferov V, Ho A, Morgello S, Yang Y, Ott J, Kreek MJ (2013) Expression of ephrin receptors and ligands in postmortem brains of HIV-infected subjects with and without cognitive impairment. J Neuroimmune Pharmacol 8:333–344PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Brandimarti R, Khan MZ, Fatatis A, Meucci O (2004) Regulation of cell cycle proteins by chemokine receptors: a novel pathway in human immunodeficiency virus neuropathogenesis? J Neurovirol 10(Suppl 1):108–112PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Ferrarese C, Aliprandi A, Tremolizzo L, Stanzani L, De Micheli A, Dolara A, Frattola L (2001) Increased glutamate in CSF and plasma of patients with HIV dementia. Neurology 57:671–675PubMedCrossRefGoogle Scholar
  93. 93.
    Meisner F, Neuen-Jacob E, Sopper S, Schmidt M, Schlammes S, Scheller C, Vosswinkel D, Ter Meulen V, Riederer P, Koutsilieri E (2008) Disruption of excitatory amino acid transporters in brains of SIV-infected rhesus macaques is associated with microglia activation. J Neurochem 104:202–209PubMedGoogle Scholar
  94. 94.
    Wang Z, Trillo-Pazos G, Kim SY, Canki M, Morgello S, Sharer LR, Gelbard HA, Su ZZ, Kang DC, Brooks AI, Fisher PB, Volsky DJ (2004) Effects of human immunodeficiency virus type 1 on astrocyte gene expression and function: potential role in neuropathogenesis. J Neurovirol 10(Suppl 1):25–32PubMedCrossRefGoogle Scholar
  95. 95.
    Potter MC, Figuera-Losada M, Rojas C, Slusher BS (2013) Targeting the glutamatergic system for the treatment of HIV-associated neurocognitive disorders. J Neuroimmune Pharmacol 8:594–607PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Melendez RI, Roman C, Capo-Velez CM, Lasalde-Dominicci JA (2016) Decreased glial and synaptic glutamate uptake in the striatum of HIV-1 gp120 transgenic mice. J Neurovirol 22:358–365PubMedCrossRefGoogle Scholar
  97. 97.
    Dreyer EB, Lipton SA (1995) The coat protein gp120 of HIV-1 inhibits astrocyte uptake of excitatory amino acids via macrophage arachidonic acid. Eur J Neurosci 7:2502–2507PubMedCrossRefGoogle Scholar
  98. 98.
    Fine SM, Angel RA, Perry SW, Epstein LG, Rothstein JD, Dewhurst S, Gelbard HA (1996) Tumor necrosis factor alpha inhibits glutamate uptake by primary human astrocytes. Implications for pathogenesis of HIV-1 dementia. J Biol Chem 271:15303–15306PubMedCrossRefGoogle Scholar
  99. 99.
    Marty V, El Hachmane M, Amedee T (2008) Dual modulation of synaptic transmission in the nucleus tractus solitarius by prostaglandin E2 synthesized downstream of IL-1beta. Eur J Neurosci 27:3132–3150PubMedCrossRefGoogle Scholar
  100. 100.
    Bellizzi MJ, Lu SM, Masliah E, Gelbard HA (2005) Synaptic activity becomes excitotoxic in neurons exposed to elevated levels of platelet-activating factor. J Clin Investig 115:3185–3192PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Lu SM, Tong N, Gelbard HA (2007) The phospholipid mediator platelet-activating factor mediates striatal synaptic facilitation. J Neuroimmune Pharmacol 2:194–201PubMedCrossRefGoogle Scholar
  102. 102.
    Bazan NG (1998) The neuromessenger platelet-activating factor in plasticity and neurodegeneration. Prog Brain Res 118:281–291PubMedCrossRefGoogle Scholar
  103. 103.
    Musante V, Summa M, Neri E, Puliti A, Godowicz TT, Severi P, Battaglia G, Raiteri M, Pittaluga A (2010) The HIV-1 viral protein Tat increases glutamate and decreases GABA exocytosis from human and mouse neocortical nerve endings. Cereb Cortex 20:1974–1984PubMedCrossRefGoogle Scholar
  104. 104.
    Perry SW, Norman JP, Litzburg A, Zhang D, Dewhurst S, Gelbard HA (2005) HIV-1 transactivator of transcription protein induces mitochondrial hyperpolarization and synaptic stress leading to apoptosis. J Immunol 174:4333–4344PubMedCrossRefGoogle Scholar
  105. 105.
    Salter MW, Dong Y, Kalia LV, Liu XJ, Pitcher G (2009) Regulation of NMDA receptors by kinases and phosphatases. In Van Dongen AM (Ed) Biology of the NMDA Receptor. Taylor & Francis Group, LLC., Boca RatonGoogle Scholar
  106. 106.
    Krogh KA, Lyddon E, Thayer SA (2014) HIV-1 Tat activates a RhoA signaling pathway to reduce NMDA-evoked calcium responses in hippocampal neurons via an actin-dependent mechanism. J Neurochem 132(3):354–366Google Scholar
  107. 107.
    Babiloni C, Buffo P, Vecchio F, Onorati P, Muratori C, Ferracuti S, Roma P, Battuello M, Donato N, Noce G, Di Campli F, Gianserra L, Teti E, Aceti A, Soricelli A, Viscione M, Andreoni M, Rossini PM, Pennica A (2014) Cortical sources of resting-state EEG rhythms in “experienced” HIV subjects under antiretroviral therapy. Clin Neurophysiol 125:1792–1802PubMedCrossRefGoogle Scholar
  108. 108.
    Modi M, Mochan A, Modi G (2009) New onset seizures in HIV—seizure semiology, CD4 counts, and viral loads. Epilepsia 50:1266–1269PubMedCrossRefGoogle Scholar
  109. 109.
    Kasyanov A, Tamamura H, Fujii N, Xiong H (2006) HIV-1 gp120 enhances giant depolarizing potentials via chemokine receptor CXCR4 in neonatal rat hippocampus. Eur J Neurosci 23:1120–1128PubMedCrossRefGoogle Scholar
  110. 110.
    Gelman BB, Spencer JA, Holzer CE 3rd, Soukup VM (2006) Abnormal striatal dopaminergic synapses in National NeuroAIDS Tissue Consortium subjects with HIV encephalitis. J Neuroimmune Pharmacol 1:410–420PubMedCrossRefGoogle Scholar
  111. 111.
    Zhu J, Ananthan S, Mactutus CF, Booze RM (2011) Recombinant human immunodeficiency virus-1 transactivator of transcription1-86 allosterically modulates dopamine transporter activity. Synapse 65:1251–1254PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Ferris MJ, Frederick-Duus D, Fadel J, Mactutus CF, Booze RM (2009) In vivo microdialysis in awake, freely moving rats demonstrates HIV-1 Tat-induced alterations in dopamine transmission. Synapse 63:181–185PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Ferris MJ, Frederick-Duus D, Fadel J, Mactutus CF, Booze RM (2009) The human immunodeficiency virus-1-associated protein, Tat1-86, impairs dopamine transporters and interacts with cocaine to reduce nerve terminal function: a no-net-flux microdialysis study. Neurosci 159:1292–1299CrossRefGoogle Scholar
  114. 114.
    Midde NM, Gomez AM, Zhu J (2012) HIV-1 Tat protein decreases dopamine transporter cell surface expression and vesicular monoamine transporter-2 function in rat striatal synaptosomes. J Neuroimmune Pharmacol 7:629–639PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Scheller C, Arendt G, Nolting T, Antke C, Sopper S, Maschke M, Obermann M, Angerer A, Husstedt IW, Meisner F, Neuen-Jacob E, Muller HW, Carey P, Ter Meulen V, Riederer P, Koutsilieri E (2010) Increased dopaminergic neurotransmission in therapy-naive asymptomatic HIV patients is not associated with adaptive changes at the dopaminergic synapses J Neural Transm 117:699–705PubMedCrossRefGoogle Scholar
  116. 116.
    Purohit V, Rapaka R, Frankenheim J, Avila A, Sorensen R, Rutter J (2013) National Institute on Drug Abuse symposium report: drugs of abuse, dopamine, and HIV-associated neurocognitive disorders/HIV-associated dementia. J Neurovirol 19:119–122PubMedCrossRefGoogle Scholar
  117. 117.
    Rock RB, Gekker G, Hu S, Sheng WS, Cheeran M, Lokensgard JR, Peterson PK (2004) Role of microglia in central nervous system infections. Clin Microbiol Rev 17:942–964PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Tremblay ME, Marker DF, Puccini JM, Muly EC, Lu SM, Gelbard HA (2013) Ultrastructure of microglia-synapse interactions in the HIV-1 Tat-injected murine central nervous system. Commun Integr Biol 6:e27670PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Lu SM, Tremblay ME, King IL, Qi J, Reynolds HM, Marker DF, Varrone JJ, Majewska AK, Dewhurst S, Gelbard HA (2011) HIV-1 Tat-induced microgliosis and synaptic damage via interactions between peripheral and central myeloid cells. PLoS ONE 6:e23915PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Mosser CA, Baptista S, Arnoux I, Audinat E (2017) Microglia in CNS development: shaping the brain for the future. Prog Neurobiol 149–150:1–20PubMedCrossRefGoogle Scholar
  121. 121.
    Hong S, Dissing-Olesen L, Stevens B (2016) New insights on the role of microglia in synaptic pruning in health and disease. Curr Opin Neurobiol 36:128–134PubMedCrossRefGoogle Scholar
  122. 122.
    Aarts MM, Tymianski M (2003) Novel treatment of excitotoxicity: targeted disruption of intracellular signalling from glutamate receptors. Biochem Pharmacol 66:877–886PubMedCrossRefGoogle Scholar
  123. 123.
    McGuire JL, Gill AJ, Douglas SD, Kolson DL (2016) The complement system, neuronal injury, and cognitive function in horizontally-acquired HIV-infected youth. J Neurovirol 22:823–830PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Collini P, Noursadeghi M, Sabroe I, Miller RF, Dockrell DH (2010) Monocyte and macrophage dysfunction as a cause of HIV-1 induced dysfunction of innate immunity. Curr Mol Med 10:727–740PubMedCrossRefGoogle Scholar
  125. 125.
    Kedzierska K, Azzam R, Ellery P, Mak J, Jaworowski A, Crowe SM (2003) Defective phagocytosis by human monocyte/macrophages following HIV-1 infection: underlying mechanisms and modulation by adjunctive cytokine therapy. J Clin Virol 26:247–263PubMedCrossRefGoogle Scholar
  126. 126.
    Debaisieux S, Lachambre S, Gross A, Mettling C, Besteiro S, Yezid H, Henaff D, Chopard C, Mesnard JM, Beaumelle B (2015) HIV-1 Tat inhibits phagocytosis by preventing the recruitment of Cdc42 to the phagocytic cup. Nat Commun 6:6211PubMedCrossRefGoogle Scholar
  127. 127.
    Krogh KA, Lyddon E, Thayer SA (2015) HIV-1 Tat activates a RhoA signaling pathway to reduce NMDA-evoked calcium responses in hippocampal neurons via an actin-dependent mechanism. J Neurochem 132:354–366PubMedCrossRefGoogle Scholar
  128. 128.
    Lin Y, Bloodgood BL, Hauser JL, Lapan AD, Koon AC, Kim TK, Hu LS, Malik AN, Greenberg ME (2008) Activity-dependent regulation of inhibitory synapse development by Npas4. Nature 455:1198–1204PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Xu C, Hermes DJ, Mackie K, Lichtman AH, Ignatowska-Jankowska BM, Fitting S (2016) Cannabinoids occlude the HIV-1 tat-induced decrease in GABAergic neurotransmission in prefrontal cortex slices. J Neuroimmune Pharmacol 11:316–331PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Xu C, Fitting S (2016) Inhibition of GABAergic Neurotransmission by HIV-1 Tat and Opioid Treatment in the Striatum Involves mu-Opioid Receptors. Front Neurosci 10:497PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Gelman BB, Chen T, Lisinicchia JG, Soukup VM, Carmical JR, Starkey JM, Masliah E, Commins DL, Brandt D, Grant I, Singer EJ, Levine AJ, Miller J, Winkler JM, Fox HS, Luxon BA (2012) The National NeuroAIDS Tissue Consortium brain gene array: two types of HIV-associated neurocognitive impairment. PLoS ONE 7:e46178PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    de San Martin JZ, Delabar JM, Bacci A, Potier MC (2017) GABAergic over-inhibition, a promising hypothesis for cognitive deficits in Down syndrome. Free Radic Biol Med 114:33–39CrossRefGoogle Scholar
  133. 133.
    Contestabile A, Magara S, Cancedda L (2017) The GABAergic hypothesis for cognitive disabilities in down syndrome. Front Cell Neurosci 11:54PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Souchet B, Guedj F, Penke-Verdier Z, Daubigney F, Duchon A, Herault Y, Bizot JC, Janel N, Creau N, Delatour B, Delabar JM (2015) Pharmacological correction of excitation/inhibition imbalance in Down syndrome mouse models. Front Behav Neurosci 9:267PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Wu Z, Guo Z, Gearing M, Chen G (2014) Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s [corrected] disease model. Nat Commun 5:4159PubMedPubMedCentralGoogle Scholar
  136. 136.
    Cavanna AE, Ali F, Rickards HE, McCorry D (2010) Behavioral and cognitive effects of anti-epileptic drugs. Discov Med 9:138–144PubMedGoogle Scholar
  137. 137.
    Xia P, Chen H-sV, Zhang D, Lipton SA (2010) Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses. J Neurosci 30:11246–11250PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Lipton SA (1992) Memantine prevents HIV coat protein-induced neuronal injury in vitro [see comments]. Neurology 42:1403–1405PubMedCrossRefGoogle Scholar
  139. 139.
    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 706:303–307PubMedCrossRefGoogle Scholar
  140. 140.
    Muller WE, Pergande G, Ushijima H, Schleger C, Kelve M, Perovic S (1996) Neurotoxicity in rat cortical cells caused by N-methyl-D-aspartate (NMDA) and gp120 of HIV-1: induction and pharmacological intervention. Prog Mol Subcell Biol 16:44–57PubMedCrossRefGoogle Scholar
  141. 141.
    Albers GW, Atkinson RP, Kelley RE, Rosenbaum DM (1995) Safety, tolerability, and pharmacokinetics of the N-methyl-D-aspartate antagonist dextrorphan in patients with acute stroke. Stroke 26:254–258 (Dextrorphan Study Group)PubMedCrossRefGoogle Scholar
  142. 142.
    Grotta J, Clark W, Coull B, Pettigrew LC, Mackay B, Goldstein LB, Meissner I, Murphy D, LaRue L (1995) Safety and tolerability of the glutamate antagonist CGS 19755 (Selfotel) in patients with acute ischemic stroke. Results of a phase IIa randomized trial. Stroke 26:602–605PubMedCrossRefGoogle Scholar
  143. 143.
    Garwood CJ, Cooper JD, Hanger DP, Noble W (2010) Anti-inflammatory impact of minocycline in a mouse model of tauopathy. Front Psychiatry 1:136PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Cheng S, Hou J, Zhang C, Xu C, Wang L, Zou X, Yu H, Shi Y, Yin Z, Chen G (2015) Minocycline reduces neuroinflammation but does not ameliorate neuron loss in a mouse model of neurodegeneration. Sci Rep 5:10535PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Garcez ML, Mina F, Bellettini-Santos T, Carneiro FG, Luz AP, Schiavo GL, Andrighetti MS, Scheid MG, Bolfe RP, Budni J (2017) Minocycline reduces inflammatory parameters in the brain structures and serum and reverses memory impairment caused by the administration of amyloid beta (1–42) in mice. Prog Neuropsychopharmacol Biol Psychiatry 77:23–31PubMedCrossRefGoogle Scholar
  146. 146.
    Si Q, Cosenza M, Kim MO, Zhao ML, Brownlee M, Goldstein H, Lee S (2004) A novel action of minocycline: inhibition of human immunodeficiency virus type 1 infection in microglia. J Neurovirol 10:284–292PubMedCrossRefGoogle Scholar
  147. 147.
    Zink MC, Uhrlaub J, DeWitt J, Voelker T, Bullock B, Mankowski J, Tarwater P, Clements J, Barber S (2005) Neuroprotective and anti-human immunodeficiency virus activity of minocycline. JAMA 293:2003–2011PubMedCrossRefGoogle Scholar
  148. 148.
    Sacktor N, Miyahara S, Deng L, Evans S, Schifitto G, Cohen BA, Paul R, Robertson K, Jarocki B, Scarsi K, Coombs RW, Zink MC, Nath A, Smith E, Ellis RJ, Singer E, Weihe J, McCarthy S, Hosey L, Clifford DB (2011) Minocycline treatment for HIV-associated cognitive impairment: results from a randomized trial. Neurology 77:1135–1142PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Nakasujja N, Miyahara S, Evans S, Lee A, Musisi S, Katabira E, Robertson K, Ronald A, Clifford DB, Sacktor N (2013) Randomized trial of minocycline in the treatment of HIV-associated cognitive impairment. Neurology 80:196–202PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Mocchetti I, Bachis A, Campbell LA, Avdoshina V (2014) Implementing neuronal plasticity in NeuroAIDS: the experience of brain-derived neurotrophic factor and other neurotrophic factors. J Neuroimmune Pharmacol 9:80–91PubMedCrossRefGoogle Scholar
  151. 151.
    Everall IP, Trillo-Pazos G, Bell C, Mallory M, Sanders V, Masliah E (2001) Amelioration of neurotoxic effects of HIV envelope protein gp120 by fibroblast growth factor: a strategy for neuroprotection. J Neuropathol Exp Neurol 60:293–301PubMedCrossRefGoogle Scholar
  152. 152.
    Fields J, Dumaop W, Langford TD, Rockenstein E, Masliah E (2014) Role of neurotrophic factor alterations in the neurodegenerative process in HIV associated neurocognitive disorders. J Neuroimmune Pharmacol 9:102–116PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Bachis A, Major EO, Mocchetti I (2003) Brain-derived neurotrophic factor inhibits human immunodeficiency virus-1/gp120-mediated cerebellar granule cell death by preventing gp120 internalization. J Neurosci 23:5715–5722PubMedGoogle Scholar
  154. 154.
    Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC, Cascio MG, Gutierrez SO, van der Stelt M, Lopez-Rodriguez ML, Casanova E, Schutz G, Zieglgansberger W, Di Marzo V, Behl C, Lutz B (2003) CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302:84–88PubMedCrossRefGoogle Scholar
  155. 155.
    Shen M, Thayer SA (1998) Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity. Mol Pharmacol 54:459–462PubMedCrossRefGoogle Scholar
  156. 156.
    Nagayama T, Sinor AD, Simon RP, Chen J, Graham SH, Jin K, Greenberg DA (1999) Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J Neurosci 19:2987–2995PubMedGoogle Scholar
  157. 157.
    Kim HJ, Waataja JJ, Thayer SA (2008) Cannabinoids inhibit network-driven synapse loss between hippocampal neurons in culture. J Pharmacol Exp Ther 325:850–858PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Purohit V, Rapaka RS, Rutter J (2014) Cannabinoid receptor-2 and HIV-associated neurocognitive disorders. J Neuroimmune Pharmacol 9:447–453PubMedCrossRefGoogle Scholar
  159. 159.
    Avraham HK, Jiang S, Fu Y, Rockenstein E, Makriyannis A, Zvonok A, Masliah E, Avraham S (2014) The cannabinoid CB(2) receptor agonist AM1241 enhances neurogenesis in GFAP/Gp120 transgenic mice displaying deficits in neurogenesis. Br J Pharmacol 171:468–479PubMedCrossRefGoogle Scholar
  160. 160.
    Gorantla S, Makarov E, Roy D, Finke-Dwyer J, Murrin LC, Gendelman HE, Poluektova L (2012) Immunoregulation of a CB2 receptor agonist in a murine model of neuroAIDS. J Neuroimmune Pharmacol 5:456–468CrossRefGoogle Scholar
  161. 161.
    Nomura DK, Morrison BE, Blankman JL, Long JZ, Kinsey SG, Marcondes MC, Ward AM, Hahn YK, Lichtman AH, Conti B, Cravatt BF (2011) Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science 334:809–813PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Kinsey SG, Wise LE, Ramesh D, Abdullah R, Selley DE, Cravatt BF, Lichtman AH (2013) Repeated low dose administration of the monoacylglycerol lipase Inhibitor JZL184 retains CB1 receptor mediated antinociceptive and gastroprotective effects. J Pharmacol Exp Ther 345:492–501PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Scheiman JM (2016) NSAID-induced gastrointestinal injury: a focused update for clinicians. J Clin Gastroenterol 50:5–10PubMedCrossRefGoogle Scholar
  164. 164.
    Ferrando SJ, Rabkin JG, van Gorp W, Lin SH, McElhiney M (2003) Longitudinal improvement in psychomotor processing speed is associated with potent combination antiretroviral therapy in HIV-1 infection. J Neuropsychiatry Clin Neurosci 15:208–214PubMedCrossRefGoogle Scholar
  165. 165.
    Thurnher MM, Schindler EG, Thurnher SA, Pernerstorfer-Schon H, Kleibl-Popov C, Rieger A (2000) Highly active antiretroviral therapy for patients with AIDS dementia complex: effect on MR imaging findings and clinical course. AJNR Am J Neuroradiol 21:670–678PubMedGoogle Scholar
  166. 166.
    Schellenberg GD, D’Souza I, Poorkaj P (2000) The genetics of Alzheimer’s disease. Curr Psychiatry Rep 2:158–164PubMedCrossRefGoogle Scholar
  167. 167.
    Corder EH, Robertson K, Lannfelt L, Bogdanovic N, Eggertsen G, Wilkins J, Hall C (1998) HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy. Nat Med 4:1182–1184PubMedCrossRefGoogle Scholar
  168. 168.
    Eugenin EA, King JE, Nath A, Calderon TM, Zukin RS, Bennett MV, Berman JW (2007) HIV-tat induces formation of an LRP-PSD-95- NMDAR-nNOS complex that promotes apoptosis in neurons and astrocytes. Proc Natl Acad Sci USA 104:3438–3443PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Keblesh JP, Dou H, Gendelman HE, Xiong H (2009) 4-Aminopyridine improves spatial memory in a murine model of HIV-1 encephalitis. J Neuroimmune Pharmacol 4:317–327PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Nakanishi N, Kang YJ, Tu S, McKercher SR, Masliah E, Lipton SA (2016) 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 58:59–65PubMedCrossRefGoogle Scholar
  171. 171.
    Meisner F, Scheller C, Kneitz S, Sopper S, Neuen-Jacob E, Riederer P, ter Meulen V, Koutsilieri E (2008) Memantine upregulates BDNF and prevents dopamine deficits in SIV-infected macaques: a novel pharmacological action of memantine. Neuropsychopharmacol 33:2228–2236CrossRefGoogle Scholar
  172. 172.
    Navia BA, Dafni U, Simpson D, Tucker T, Singer E, McArthur JC, Yiannoutsos C, Zaborski L, Lipton SA (1998) A phase I/II trial of nimodipine for HIV-related neurologic complications. Neurology 51:221–228PubMedCrossRefGoogle Scholar
  173. 173.
    Heaton RK, Franklin DR, Ellis RJ, McCutchan JA, Letendre SL, Leblanc S, Corkran SH, Duarte NA, Clifford DB, Woods SP, Collier AC, Marra CM, Morgello S, Mindt MR, Taylor MJ, Marcotte TD, Atkinson JH, Wolfson T, Gelman BB, McArthur JC, Simpson DM, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I (2011) HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol 17:3–16PubMedCrossRefGoogle Scholar
  174. 174.
    Schifitto G, Yiannoutsos CT, Simpson DM, Marra CM, Singer EJ, Kolson DL, Nath A, Berger JR, Navia B, Group Actg 301 Team AA (2006) A placebo-controlled study of memantine for the treatment of human immunodeficiency virus-associated sensory neuropathy. J Neurovirol 12:328–331PubMedCrossRefGoogle Scholar
  175. 175.
    Schifitto G, Navia BA, Yiannoutsos CT, Marra CM, Chang L, Ernst T, Jarvik JG, Miller EN, Singer EJ, Ellis RJ, Kolson DL, Simpson D, Nath A, Berger J, Shriver SL, Millar LL, Colquhoun D, Lenkinski R, Gonzalez RG, Lipton SA (2007) Memantine and HIV-associated cognitive impairment: a neuropsychological and proton magnetic resonance spectroscopy study. AIDS 21:1877–1886PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PharmacologyUniversity of Minnesota Medical SchoolMinneapolisUSA

Personalised recommendations