Abstract
BACKGROUND
Huntington’s Disease (HD) is an autosomal dominant neurodegenerative disease causing severe neurodegeneration of the striatum as well as marked cognitive and motor disabilities. Excitotoxicity, caused by overstimulation of NMDA receptors (NMDARs) has been shown to have a key role in the neuropathogenesis of HD, suggesting that targeting NMDAR-dependent signaling may be an effective clinical approach for HD. However, broad NMDAR antagonists are generally poor therapeutics in clinical practice. It has been suggested that GluN2A-containing, synaptically located NMDARs activate cell survival signaling pathways, while GluN2B-containing, primarily extrasynaptic NMDARs trigger cell death signaling. A better approach to development of effective therapeutics for HD may be to target, specifically, the cell-death specific pathways associated with extrasynaptic GluN2B NMDAR activation, while maintaining or potentiating the cellsurvival activity of GluN2A-NMDARs.
OBJECTIVE
This review outlines the role of NMDAR-mediated excitotoxicity in HD and overviews current efforts to develop better therapeutics for HD where NMDAR excitotoxicity is the target.
METHODS
A systematic review process was conducted using the PubMed search engine focusing on research conducted in the past 5-10 years. 235 articles were consulted for the review, with key search terms including “Huntington’s Disease,” “excitotoxicity,” “NMDAR” and “therapeutics.”
RESULTS
A wide range of NMDAR excitotoxicity-based targets for HD were identified and reviewed, including targeting NMDARs directly by blocking GluN2B, extrasynaptic NMDARs and/or potentiating GluN2A, synaptic NMDARs, targeting glutamate release or uptake, or targeting specific downstream cell-death signaling of NMDARs.
CONCLUSION
The current review identifies NMDAR-mediated excitotoxicity as a key player in HD pathogenesis and points to various excitotoxicity-focused targets as potential future preventative therapeutics for HD.
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References
Aamodt S M, Constantine-Paton M (1999). The role of neural activity in synaptic development and its implications for adult brain function. Adv Neurol, 79: 133–144
Aarts M, Liu Y, Liu L, Besshoh S, Arundine M, Gurd J W, Wang Y T, Salter M W, Tymianski M (2002). Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions. Science, 298(5594): 846–850
Abiltrub M, Shattock M (2013). Cardiac dysautonomia in Huntington’s disease. J Huntington Dis, 2(3): 251–261
Akazawa C, Shigemoto R, Bessho Y, Nakanishi S, Mizuno N (1994). Differential expression of five N-methyl-D-aspartate receptor subunit mRNAs in the cerebellum of developing and adult rats. J Comp Neurol, 347(1): 150–160
Albin R L, Young A B, Penney J B, Handelin B, Balfour R, Anderson K D, Markel D S, Tourtellotte WW, Reiner A (1990). Abnormalities of striatal projection neurons and N-methyl-D-aspartate receptors in presymptomatic Huntington’s disease. N Engl J Med, 322(18): 1293–1298
Arai A, Vanderklish P, Kessler M, Lee K, Lynch G (1991). A brief period of hypoxia causes proteolysis of cytoskeletal proteins in hippocampal slices. Brain Res, 555(2): 276–280
Arlinghaus L, Mehdi S, Lee K S (1991). Improved posthypoxic recovery with a membrane-permeable calpain inhibitor. Eur J Pharmacol, 209 (1-2): 123–125
Balázs R, Hack N, Jørgensen O S (1988). Stimulation of the receptor has a trophic effect on differentiating cerebellar granule cells. Neurosci Lett, 87 (1–2): 80–86
Balázs R, Hack N, Jørgensen O S ( 1990). Interactive effects involving different classes of excitatory amino acid receptors and the survival of cerebellar granule cells in culture. Int J Dev Neurosci, 8(4): 347–359
Balázs R, Hack N, Jørgensen O S, Cotman C W (1989). N-methyl-Daspartate promotes the survival of cerebellar granule cells: pharmacological characterization. Neurosci Lett, 101(3): 241–246
Balázs R, Jørgensen O S, Hack N (1988). N-methyl-D-aspartate promotes the survival of cerebellar granule cells in culture. Neuroscience, 27(2): 437–451
Bano D, Young K W, Guerin C J, Lefeuvre R, Rothwell N J, Naldini L, Rizzuto R, Carafoli E, Nicotera P (2005). Cleavage of the plasma membrane Na+/Ca2+ exchanger in excitotoxicity. Cell, 120(2): 275–285
Beal M F (1998). Excitotoxicity and nitric oxide in Parkinson’s disease pathogenesis. Ann Neurol, 44 (3 Suppl 1): S110–S114
Beal MF, Kowall NW, Ellison DW, Mazurek MF, Swartz K J, Martin J B (1986). Replication of the neurochemical characteristics of Huntington’s disease by quinolinic acid. Nature, 321(6066): 168–171
Beighton P, Hayden M R (1981). Huntington’s chorea. S Afr Med J, 59 (8): 250
Benveniste M, Mayer M L (1991). Kinetic analysis of antagonist action at N-methyl-D-aspartic acid receptors. Two binding sites each for glutamate and glycine. Biophys J, 59(3): 560–573
Berliocchi L, Bano D, Nicotera P (2005). Ca2+ signals and death programmes in neurons. Philos Trans R Soc Lond B Biol Sci, 360(1464): 2255–2258
Bliss T V P, Collingridge G L (1993). A synaptic model of memory: long-term potentiation in the hippocampus. Nature, 361(6407): 31–39
Brenman J E, Chao D S, Gee S H, McGee A W, Craven S E, Santillano D R, Wu Z, Huang F, Xia H, Peters M F, Froehner S C, Bredt D S (1996). Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and alpha1-syntrophin mediated by PDZ domains. Cell, 84(5): 757–767
Brenneman D E, Forsythe I D, Nicol T, Nelson P G (1990a). N-methyl- D-aspartate receptors influence neuronal survival in developing spinal cord cultures. Brain Res Dev Brain Res, 51(1): 63–68
Brenneman D E, Yu C, Nelson P G (1990b). Multi-determinate regulation of neuronal survival: neuropeptides, excitatory amino acids and bioelectric activity. Int J Dev Neurosci, 8(4): 371–378
Burde R M, Schainker B, Kayes J (1971). Acute effect of oral and subcutaneous administration of monosodium glutamate on the arcuate nucleus of the hypothalamus in mice and rats. Nature, 233(5314): 58–60
Burns L H, Pakzaban P, Deacon TW, Brownell A L, Tatter S B, Jenkins B G, Isacson O (1995). Selective putaminal excitotoxic lesions in non-human primates model the movement disorder of Huntington disease. Neuroscience, 64(4): 1007–1017
Carroll J, Southwell A L, Graham R K, Lerch J P, Ehrnhoefer D E, Cao L P, Zhang W N, Deng Y, Bissada N, Henkelman R M, Hayden M R (2011). Mice lacking caspase-2 are protected from behavioral changes, but not pathology, in the YAC128 model of Huntington disease. Moler Neurodegener, 6 (1): 59
Cepeda C, Hurst R S, Calvert C R, Hernndez-Echeagaray E, Nguyen O K, Jocoy E, Christian L J, Ariano MA, Levine MS (2003). Transient and progressive electrophysiological alterations in the corticostriatal pathway in a mouse model of Huntington’s disease. J Neurosci, 23(3): 961–969
Cepeda C, Itri J N, Flores-Hernández J, Hurst R S, Calvert C R, Levine M S (2001). Differential sensitivity of medium- and large-sized striatal neurons to NMDA but not kainate receptor activation in the rat. Eur J Neurosci, 14(10): 1577–1589
Chapman D E, Keefe K A, Wilcox K S (2003). Evidence for functionally distinct synaptic NMDA receptors in ventromedial versus dorsolateral striatum. J Neurophysiol, 89(1): 69–80
Chen M, Lu T J, Chen X J, Zhou Y, Chen Q, Feng X Y, Xu L, Duan W H, Xiong Z Q (2008). Differential roles of NMDA receptor subtypes in ischemic neuronal cell death and ischemic tolerance. Stroke, 39(11): 3042–3048
Chen M, Ona V O, Li M, Ferrante R J, Fink K B, Zhu S, Bian J, Guo L, Farrell L A, Hersch S M, Hobbs W, Vonsattel J P, Cha J H, Friedlander RM (2000). Minocycline inhibits caspase-1 and caspase- 3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med, 6(7): 797–801
Chen N, Luo T, Wellington C, Metzler M, McCutcheon K, Hayden MR, Raymond L A (1999). Subtype-specific enhancement of NMDA receptor currents by mutant huntingtin. J Neurochem, 72(5): 1890–1898
Choi D W (1995). Calcium: still center-stage in hypoxic-ischemic neuronal death. Trends Neurosci, 18(2): 58–60
Choi D W, Koh J Y, Peters S (1988). Pharmacology of glutamate neurotoxicity in cortical cell culture: attenuation by NMDA antagonists. J Neurosci, 8(1): 185–196
Clements J D, Westbrook G L (1991). Activation kinetics reveal the number of glutamate and glycine binding sites on the N-methyl-Daspartate receptor. Neuron, 7(4): 605–613
Cottrell J R, Dubé G R, Egles C, Liu G (2000). Distribution, density, and clustering of functional glutamate receptors before and after synaptogenesis in hippocampal neurons. J Neurophysiol, 84(3): 1573–1587
Cowan C M, Fan M M, Fan J, Shehadeh J, Zhang L Y, Graham R K, Hayden M R, Raymond L A (2008). Polyglutamine-modulated striatal calpain activity in YAC transgenic huntington disease mouse model: impact on NMDA receptor function and toxicity. J Neurosci, 28(48): 12725–12735
Coyle J T, Schwarcz R (1976). Lesion of striatal neurones with kainic acid provides a model for Huntington’s chorea. Nature, 263(5574): 244–246
Craven S E, El-Husseini A E, Bredt D S (1999). Synaptic targeting of the postsynaptic density protein PSD-95 mediated by lipid and protein motifs. Neuron, 22(3): 497–509
Cross A J, Slater P, Reynolds G P (1986). Reduced high-affinity glutamate uptake sites in the brains of patients with Huntington’s disease. Neurosci Lett, 67(2): 198–202
Cull-Candy S, Brickley S, Farrant M (2001). NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol, 11(3): 327–335
Cull-Candy S G, Leszkiewicz D N (2004). Role of distinct NMDA receptor subtypes at central synapses. Sci STKE, 2004 (255): re16
Dau A, Gladding C M, Sepers M D, Raymond L A (2014). Chronic blockade of extrasynaptic NMDA receptors ameliorates synaptic dysfunction and pro-death signaling in Huntington disease transgenic mice. Neurobiol Dis, 62: 533–542
De Ridder M N, Simon M J, Siman R, Auberson Y P, Raghupathi R, Meaney D F (2006). Traumatic mechanical injury to the hippocampus in vitro causes regional caspase-3 and calpain activation that is influenced by NMDA receptor subunit composition. Neurobiol Dis, 22(1): 165–176
Didier M, Roux P, Piechaczyk M, Verrier B, Bockaert J, Pin J P (1989). Cerebellar granule cell survival and maturation induced by K + and NMDA correlate with c-fos proto-oncogene expression. Neurosci Lett, 107 (1-3): 55–62
Di Figlia M (1990). Excitotoxic injury of the neostriatum: a model for Huntington’s disease. Trends Neurosci, 13(7): 286–289
Dingledine R, Borges K, Bowie D, Traynelis S F (1999). The glutamate receptor ion channels. Pharmacol Rev, 51(1): 7–61
Dragunow M, Faull R L, Lawlor P, Beilharz E J, Singleton K, Walker E B, Mee E (1995). In situ evidence for DNA fragmentation in Huntington’s disease striatum and Alzheimer’s disease temporal lobes. Neuroreport, 6(7): 1053–1057
Ehrlich M E (2012). Huntington’s disease and the striatal medium spiny neuron: cell-autonomous and non-cell-autonomous mechanisms of disease. Neurotherapeutics, 9(2): 270–284
El-Husseini A E, Schnell E, Chetkovich D M, Nicoll R A, Bredt D S (2000). PSD-95 involvement in maturation of excitatory synapses. Science, 290(5495): 1364–1368
Faideau M, Kim J, Cormier K, Gilmore R, Welch M, Auregan G, Dufour N, Guillermier M, Brouillet E, Hantraye P, Déglon N, Ferrante R J, Bonvento G (2010). In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington’s disease subjects. Hum Mol Genet, 19(15): 3053–3067
Fan J, Cowan C M, Zhang L Y, Hayden M R, Raymond L A (2009). Interaction of postsynaptic density protein-95 with NMDA receptors influences excitotoxicity in the yeast artificial chromosome mouse model of Huntington’s disease. J Neurosci, 29(35): 10928–10938
Fan M M Y, Fernandes H B, Zhang L Y, Hayden M R, Raymond L A (2007). Altered NMDA receptor trafficking in a yeast artificial chromosome transgenic mouse model of Huntington’s disease. J Neurosci, 27(14): 3768–3779
Fan M M Y, Raymond L A (2007). N-methyl-D-aspartate (NMDA) receptor function and excitotoxicity in Huntington’s disease. Prog Neurobiol, 81 (5-6): 272–293
Fan X, Jin W Y, Lu J, Wang J, Wang Y T (2014). Rapid and reversible knockdown of endogenous proteins by peptide-directed lysosomal degradation. Nat Neurosci, 17(3): 471–480
Ferrante R J, Kowall NW, BealMF, Martin J B, Bird E D, Richardson E P (1987). Morphologic and histochemical characteristics of a spared subset of striatal neurons in Huntington’s disease. J Neuropathol Exp Neurol, 46(1): 12–27
Ferrante R J, Kowall N W, Cipolloni P B, Storey E, Beal M F (1993). Excitotoxin lesions in primates as a model for Huntington’s disease: histopathologic and neurochemical characterization. Exp Neurol, 119(1): 46–71
Fischer G, Mutel V, Trube G, Malherbe P, Kew J N, Mohacsi E, HeitzM P, Kemp J A (1997). Ro 25-6981, a highly potent and selective blocker of N-methyl-D-aspartate receptors containing the NR2B subunit. Characterization in vitro. J Pharmacol Exp Ther, 283(3): 1285–1292
Flint A C, Maisch U S, Weishaupt J H, Kriegstein A R, Monyer H (1997). NR2A subunit expression shortens NMDA receptor synaptic currents in developing neocortex. J Neurosci, 17(7): 2469–2476
Foster K A, McLaughlin N, Edbauer D, Phillips M, Bolton A, Constantine-Paton M, Sheng M (2010). Distinct roles of NR2A and NR2B cytoplasmic tails in long-term potentiation. J Neurosci, 30(7): 2676–2685
Franklin J L, Johnson E M Jr (1992). Suppression of programmed neuronal death by sustained elevation of cytoplasmic calcium. Trends Neurosci, 15(12): 501–508
Freedman J K, Potts A M (1962). Repression of glutaminase I in the rat retina by administration of sodium-L-glutamate. Invest Ophthalmol, 1: 118–121
Friedman L K (2006). Calcium: a role for neuroprotection and sustained adaptation. Mol Interv, 6(6): 315–329
Gafni J, Ellerby L M (2002). Calpain activation in Huntington’s disease. J Neurosci, 22(12): 4842–4849
Gallagher M J, Huang H, Pritchett D B, Lynch D R (1996). Interactions between ifenprodil and the NR2B subunit of the N-methyl-Daspartate receptor. J Biol Chem, 271(16): 9603–9611
Gascón S, Sobrado M, Roda J M, Rodríguez-Peña A, Díaz-Guerra M (2008). Excitotoxicity and focal cerebral ischemia induce truncation of the NR2A and NR2B subunits of the NMDA receptor and cleavage of the scaffolding protein PSD-95. Mol Psychiatry, 13(1): 99–114
Gladding C M, Fan J, Zhang L Y, Wang L, Xu J, Li E H, Lombroso P J, Raymond L A (2014). Alterations in STriatal-Enriched protein tyrosine Phosphatase expression, activation, and downstream signaling in early and late stages of the YAC128 Huntington’s disease mouse model. J Neurochem, 130(1): 145–159
Gladding C M, Raymond L A (2011). Mechanisms underlying NMDA receptor synaptic/extrasynaptic distribution and function. Mol Cell Neurosci, 48(4): 308–320
Gladding C M, Sepers M D, Xu J, Zhang L Y, Milnerwood A J, Lombroso P J, Raymond L A (2012). Calpain and STriatal-Enriched protein tyrosine phosphatase (STEP) activation contribute to extrasynaptic NMDA receptor localization in a Huntington’s disease mouse model. Hum Mol Genet, 21(17): 3739–3752
Gotti B, Duverger D, Bertin J, Carter C, Dupont R, Frost J, Gaudilliere B, MacKenzie E T, Rousseau J, Scatton B, et al (1988). Ifenprodil and SL 82.0715 as cerebral anti-ischemic agents. I. Evidence for efficacy in models of focal cerebral ischemia. J Pharmacol Exp Ther, 247(3): 1211–1221
Gouix E, Léveillé F, Nicole O, Melon C, Had-Aissouni L, Buisson A (2009). Reverse glial glutamate uptake triggers neuronal cell death through extrasynaptic NMDA receptor activation. Mol Cell Neurosci, 40(4): 463–473
Graham D, Darles J, Langer S (1992). The neuroprotective properties of ifenprodil, a novel NMDA receptor antagonist, in neuronal cell culture toxicity studies. Eur J Pharmacol, 226(4): 373–376
Graham R K, Deng Y, Carroll J, Vaid K, Cowan C, Pouladi M A, Metzler M, Bissada N, Wang L, Faull R L, Gray M, Yang X W, Raymond L A, Hayden M R (2010). Cleavage at the 586 amino acid caspase-6 site in mutant huntingtin influences caspase-6 activation in vivo. J Neurosci, 30(45): 15019–15029
Graham R K, Deng Y, Slow E J, Haigh B, Bissada N, Lu G, Pearson J, Shehadeh J, Bertram L, Murphy Z, Warby S C, Doty C N, Roy S, Wellington C L, Leavitt B R, Raymond L A, Nicholson DW, Hayden M R (2006a). Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell, 125(6): 1179–1191
Graham R K, Ehrnhoefer D E, Hayden M R (2011). Caspase-6 and neurodegeneration. Trends Neurosci, 34(12): 646–656
Graham R K, Pouladi M A, Joshi P, Lu G, Deng Y, Wu N P, Figueroa B E, Metzler M, Andr V M, Slow E J, Raymond L, Friedlander R, Levine M S, Leavitt B R, Hayden M R (2009). Differential susceptibility to excitotoxic stress in YAC128 mouse models of Huntington disease between initiation and progression of disease. J Neurosci, 29(7): 2193–2204
Graham R K, Slow E J, Deng Y, Bissada N, Lu G, Pearson J, Shehadeh J, Leavitt B R, Raymond L A, Hayden M R (2006b). Levels of mutant huntingtin influence the phenotypic severity of Huntington disease in YAC128 mouse models. Neurobiol Dis, 21(2): 444–455
Graveland G A, Williams R S, Di Figlia M (1985). Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington’s disease. Science, 227(4688): 770–773
Groc L, Heine M, Cousins S L, Stephenson F A, Lounis B, Cognet L, Choquet D (2006). NMDA receptor surface mobility depends on NR2A-2B subunits. Proc Natl Acad Sci U S A, 103(49): 18769–18774
Grossberg G T, Thomas S J (2009). Memantine: a review of studies into its safety and efficacy in treating Alzheimer's disease and other dementias. Clin Interv Aging, 4: 367–377
Guidetti P, Bates G P, Graham R K, Hayden M R, Leavitt B R, MacDonald M E, Slow E J, Wheeler V C, Woodman B, Schwarcz R (2006). Elevated brain 3-hydroxykynurenine and quinolinate levels in Huntington disease mice. Neurobiol Dis, 23(1): 190–197
Guidetti P, Luthi-Carter R E, Augood S J, Schwarcz R (2004). Neostriatal and cortical quinolinate levels are increased in early grade Huntington’s disease. Neurobiol Dis, 17(3): 455–461
Guttmann R P, Baker D L, Seifert K M, Cohen A S, Coulter D A, Lynch D R (2001). Specific proteolysis of the NR2 subunit at multiple sites by calpain. J Neurochem, 78(5): 1083–1093
Guttmann R P, Sokol S, Baker D L, Simpkins K L, Dong Y, Lynch D R (2002). Proteolysis of the N-methyl-d-aspartate receptor by calpain in situ. J Pharmacol Exp Ther, 302(3): 1023–1030
Hansson O, Guatteo E, Mercuri N B, Bernardi G, Li X J, Castilho R F, Brundin P (2001). Resistance to NMDA toxicity correlates with appearance of nuclear inclusions, behavioural deficits and changes in calcium homeostasis in mice transgenic for exon 1 of the huntington gene. Eur J Neurosci, 14(9): 1492–1504
Hantraye P, Riche D, Maziere M, Isacson O (1990). A primate model of Huntington’s disease: behavioral and anatomical studies of unilateral excitotoxic lesions of the caudate-putamen in the baboon. Exp Neurol, 108(2): 91–104
Hardingham G E, Bading H (2003). The Yin and Yang of NMDA receptor signalling. Trends Neurosci, 26(2): 81–89
Hardingham G E, Bading H (2010). Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci, 11(10): 682–696
Hardingham G E, Fukunaga Y, Bading H (2002). Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci, 5(5): 405–414
Harjes P, Wanker E E (2003). The hunt for huntingtin function: interaction partners tell many different stories. Trends Biochem Sci, 28(8): 425–433
Harris A Z, Pettit D L (2007). Extrasynaptic and synaptic NMDA receptors form stable and uniform pools in rat hippocampal slices. J Physiol, 584 (Pt 2): 509–519
Hassel B, Tessler S, Faull R L, Emson P C (2008). Glutamate uptake is reduced in prefrontal cortex in Huntington’s disease. Neurochem Res, 33(2): 232–237
Hayashi T, Thomas G M, Huganir R L (2009). Dual palmitoylation of NR2 subunits regulates NMDA receptor trafficking. Neuron, 64(2): 213–226
Heinsen H, Rüb U, Gangnus D, Jungkunz G, Bauer M, Ulmar G, Bethke B, Schüler M, Böcker F, Eisenmenger W, Götz M, Strik M (1996). Nerve cell loss in the thalamic centromedian-parafascicular complex in patients with Huntington’s disease. Acta Neuropathol, 91(2): 161–168
Hermel E, Gafni J, Propp S S, Leavitt B R, Wellington C L, Young J E, Hackam A S, Logvinova A V, Peel A L, Chen S F, Hook V, Singaraja R, Krajewski S, Goldsmith P C, Ellerby HM, HaydenMR, Bredesen D E, Ellerby L M (2004). Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington’s disease. Cell Death Differ, 11(4): 424–438
Hodges A, Strand A D, Aragaki A K, Kuhn A, Sengstag T, Hughes G, Elliston L A, Hartog C, Goldstein D R, Thu D, Hollingsworth Z R, Collin F, Synek B, Holmans P A, Young A B, Wexler N S, Delorenzi M, Kooperberg C, Augood S J, Faull R L, Olson JM, Jones L, Luthi-Carter R (2006). Regional and cellular gene expression changes in human Huntington’s disease brain. Hum Mol Genet, 15(6): 965–977
Hodgson J G, Agopyan N, Gutekunst C A, Leavitt B R, Le Piane F, Singaraja R, Smith D J, Bissada N, McCutcheon K, Nasir J, Jamot L, Li X J, Stevens M E, Rosemond E, Roder J C, Phillips A G, Rubin E M, Hersch S M, Hayden M R (1999). A YAC mouse model for Huntington’s disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron, 23(1): 181–192
Howard R, McShane R, Lindesay J, Ritchie C, Baldwin A, Barber R, Burns A, Dening T, Findlay D, Holmes C, Hughes A, Jacoby R, Jones R, Jones R, McKeith I, Macharouthu A, O’Brien J, Passmore P, Sheehan B, Juszczak E, Katona C, Hills R, Knapp M, Ballard C, Brown R, Banerjee S, Onions C, Griffin M, Adams J, Gray R, Johnson T, Bentham P, Phillips P (2012). Donepezil and memantine for moderate-to-severe Alzheimer’s disease. N Engl J Med, 366(10): 893–903
Huang K, KangMH, Askew C, Kang R, Sanders S S, Wan J, Davis N G, Hayden M R (2010). Palmitoylation and function of glial glutamate transporter-1 is reduced in the YAC128 mouse model of Huntington disease. Neurobiol Dis, 40(1): 207–215
Huang K, Yanai A, Kang R, Arstikaitis P, Singaraja R R, Metzler M, Mullard A, Haigh B, Gauthier-Campbell C, Gutekunst C A, Hayden MR, El-Husseini A (2004). Huntingtin-interacting protein HIP14 is a palmitoyl transferase involved in palmitoylation and trafficking of multiple neuronal proteins. Neuron, 44(6): 977–986
Hynd M R, Scott H L, Dodd P R (2004). Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer’s disease. Neurochem Int, 45(5): 583–595
Ikonomidou C, Turski L (2002). Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury? Lancet Neurol, 1(6): 383–386
Ishii T, Moriyoshi K, Sugihara H, Sakurada K, Kadotani H, Yokoi M, Akazawa C, Shigemoto R, Mizuno N, Masu M, et al (1993). Molecular characterization of the family of the N-methyl-D-aspartate receptor subunits. J Biol Chem, 268(4): 2836–2843
Izumi Y, Tokuda K, Zorumski C F (2008). Long-term potentiation inhibition by low-level N-methyl-D-aspartate receptor activation involves calcineurin, nitric oxide, and p38 mitogen-activated protein kinase. Hippocampus, 18(3): 258–265
Jarabek B R (2003). Regulation of proteins affecting NMDA receptorinduced excitotoxicity in a Huntington’s mouse model. Brain, 127(3): 505–516
Johnson J W, Ascher P (1987). Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature, 325(6104): 529–531
Johnston M V (2005). Excitotoxicity in perinatal brain injury. Brain Pathol, 15(3): 234–240
Kaltenbach L S, Romero E, Becklin R R, Chettier R, Bell R, Phansalkar A, Strand A, Torcassi C, Savage J, Hurlburt A, Cha G H, Ukani L, Chepanoske C L, Zhen Y, Sahasrabudhe S, Olson J, Kurschner C, Ellerby L M, Peltier J M, Botas J, Hughes R E (2007). Huntingtin interacting proteins are genetic modifiers of neurodegeneration. PLoS Genet, 3 (5): e82
Kandel E R, Schwartz J H, Jessell T M (1995). Essentials of Neural Science and Behavior. McGraw Hill Professional
Kassubek J, Bernhard Landwehrmeyer G, Ecker D, Juengling F D, Muche R, Schuller S, Weindl A, Peinemann A (2004). Global cerebral atrophy in early stages of Huntington’s disease: quantitative MRI study. Neuroreport, 15(2): 363–365
Katagiri H, Tanaka K, Manabe T (2001). Requirement of appropriate glutamate concentrations in the synaptic cleft for hippocampal LTP induction. Eur J Neurosci, 14(3): 547–553
Katsura K, Ekholm A, Siesjö B K (1992). Coupling among changes in energy metabolism, acid-base homeostasis, and ion fluxes in ischemia. Can J Physiol Pharmacol, 70 (Suppl): S170–S175
Kaufman AM, Milnerwood A J, Sepers MD, Coquinco A, She K, Wang L, Lee H, Craig A M, Cynader M, Raymond L A (2012). Opposing roles of synaptic and extrasynaptic NMDA receptor signaling in cocultured striatal and cortical neurons. J Neurosci, 32(12): 3992–4003
Kew J N, Trube G, Kemp J A (1996). A novel mechanism of activitydependent NMDA receptor antagonism describes the effect of ifenprodil in rat cultured cortical neurones. J Physiol, 497 (Pt 3): 761–772
Kim M, Velier J, Chase K, Laforet G, Kalchman M A, Hayden M R, Won L, Heller A, Aronin N, Difiglia M (1999). Forskolin and dopamine D1 receptor activation increase huntingtin’s association with endosomes in immortalized neuronal cells of striatal origin. Neuroscience, 89(4): 1159–1167
Klapstein G J, Fisher R S, Zanjani H, Cepeda C, Jokel E S, Chesselet M F, Levine M S (2001). Electrophysiological and morphological changes in striatal spiny neurons in R6/2 Huntington’s disease transgenic mice. J Neurophysiol, 86(6): 2667–2677
Koike T, Martin D P, Johnson E M (1989). Role of Ca2+ channels in the ability of membrane depolarization to prevent neuronal death induced by trophic-factor deprivation: evidence that levels of internal Ca2+ determine nerve growth factor dependence of sympathetic ganglion cells. Proc Natl Acad Sci U S A, 86(16): 6421–6425
Kornau H C, Schenker L T, Kennedy MB, Seeburg P H (1995). Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science, 269(5231): 1737–1740
Koutsilieri E, Riederer P (2007). Excitotoxicity and new antiglutamatergic strategies in Parkinson’s disease and Alzheimer’s disease. Parkinsonism Relat Disord, 13 (Suppl 3): S329–S331
Kremer B, Clark C M, Almqvist E W, Raymond L A, Graf P, Jacova C, Mezei M, Hardy M A, Snow B, Martin W, Hayden M R (1999). Influence of lamotrigine on progression of early Huntington disease: a randomized clinical trial. Neurology, 53(5): 1000–1011
Kutsuwada T, Kashiwabuchi N, Mori H, Sakimura K, Kushiya E, Araki K, Meguro H, Masaki H, Kumanishi T, Arakawa M, Mishina M (1992). Molecular diversity of the NMDA receptor channel. Nature, 358(6381): 36–41
Lai T W, Wang Y T (2010). Fashioning drugs for stroke. Nat Med, 16(12): 1376–1378
Lai T W, Zhang S, Wang Y T (2014). Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog Neurobiol, 115: 157–188
Lan J Y, Skeberdis V A, Jover T, Grooms S Y, Lin Y, Araneda R C, Zheng X, Bennett M V, Zukin R S (2001). Protein kinase C modulates NMDA receptor trafficking and gating. Nat Neurosci, 4(4): 382–390
Lee K S, Frank S, Vanderklish P, Arai A, Lynch G (1991). Inhibition of proteolysis protects hippocampal neurons from ischemia. Proc Natl Acad Sci U S A, 88(16): 7233–7237
Lee M S, Kwon Y T, Li M, Peng J, Friedlander R M, Tsai L H (2000). Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature, 405(6784): 360–364
Lester R A J, Clements J D, Westbrook G L, Jahr C E (1990). Channel kinetics determine the time course of NMDA receptor-mediated synaptic currents. Nature, 346(6284): 565–567
Levine M S, Klapstein G J, Koppel A, Gruen E, Cepeda C, Vargas M E, Jokel E S, Carpenter E M, Zanjani H, Hurst R S, Efstratiadis A, Zeitlin S, ChesseletMF (1999). Enhanced sensitivity to N-methyl-Daspartate receptor activation in transgenic and knockin mouse models of Huntington's disease. J Neurosci Res, 58 (4):515–532
Levine M S, Klapstein G J, Koppel A, Gruen E, Cepeda C, Vargas M E, Jokel E S, Carpenter E M, Zanjani H, Hurst R S, Efstratiadis A, Zeitlin S, ChesseletMF (1999). Enhanced sensitivity to N-methyl-Daspartate receptor activation in transgenic and knockin mouse models of Huntington’s disease. J Neurosci Res, 58(4): 515–532
Li J H, Wang Y H, Wolfe B B, Krueger K E, Corsi L, Stocca G, Vicini S (1998). Developmental changes in localization of NMDA receptor subunits in primary cultures of cortical neurons. Eur J Neurosci, 10(5): 1704–1715
Li L, Murphy T H, Hayden M R, Raymond L A (2004). Enhanced striatal NR2B-containing N-methyl-D-aspartate receptor-mediated synaptic currents in a mouse model of Huntington disease. J Neurophysiol, 92(5): 2738–2746
Li X, Standley C, Sapp E, Valencia A, Qin Z H, Kegel K B, Yoder J, Comer-Tierney L A, Esteves M, Chase K, Alexander J, Masso N, Sobin L, Bellve K, Tuft R, Lifshitz L, Fogarty K, Aronin N, Di Figlia M (2009). Mutant Huntingtin Impairs Vesicle Formation from Recycling Endosomes by Interfering with Rab11 Activity. Mol Cell Biol, 29(22): 6106–6116
Li S, Jin M, Koeglsperger T, Shepardson N E, Shankar G M, Selkoe D J (2011). Soluble Aß oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2 Bcontaining NMDA receptors. J Neurosci, 31(8): 6627–6638
Liévens J C, Woodman B, Mahal A, Spasic-Boscovic O, Samuel D, Kerkerian-Le Goff L, Bates G P (2001). Impaired glutamate uptake in the R6 Huntington’s disease transgenic mice. Neurobiol Dis, 8(5): 807–821
Lim D, Fedrizzi L, Tartari M, Zuccato C, Cattaneo E, Brini M, Carafoli E (2008). Calcium homeostasis and mitochondrial dysfunction in striatal neurons of Huntington disease. J Biol Chem, 283(9): 5780–5789
Lin Y, Skeberdis V A, Francesconi A, Bennett M V, Zukin R S (2004). Postsynaptic density protein-95 regulates NMDA channel gating and surface expression. J Neurosci, 24(45): 10138–10148
Lipton S A (2004a). Failures and successes of NMDA receptor antagonists: molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults. NeuroRx, 1(1): 101–110
Lipton S A (2004b). Paradigm shift in NMDA receptor antagonist drug development: molecular mechanism of uncompetitive inhibition by memantine in the treatment of Alzheimer’s disease and other neurologic disorders. J Alzheimers Dis, 6 (6 Suppl): S61–S74
Liu D D, Yang Q, Li S T (2013). Activation of extrasynaptic NMDA receptors induces LTD in rat hippocampal CA1 neurons. Brain Res Bull, 93: 10–16
Liu L, Wong T P, Pozza M F, Lingenhoehl K, Wang Y, Sheng M, Auberson Y P, Wang Y T (2004). Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science, 304(5673): 1021–1024
Liu Y, Wong T P, Aarts M, Rooyakkers A, Liu L, Lai T W, Wu D C, Lu J, Tymianski M, Craig A M, Wang Y T (2007). NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J Neurosci, 27(11): 2846–2857
López-Menéndez C, Gascón S, Sobrado M, Vidaurre O G, Higuero AM, Rodríguez-Peña A, Iglesias T, Díaz-Guerra M (2009). Kidins220/ ARMS downregulation by excitotoxic activation of NMDARs reveals its involvement in neuronal survival and death pathways. J Cell Sci, 122 (Pt 19): 3554–3565
Lu W, Man H, Ju W, Trimble W S, MacDonald J F, Wang Y T (2001). Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons. Neuron, 29(1): 243–254
Lucas D R, Newhouse J P (1957). The toxic effect of sodium Lglutamate on the inner layers of the retina. AMA Arch Ophthalmol, 58(2): 193–201
MacDermott A B, Mayer M L, Westbrook G L, Smith S J, Barker J L (1986). NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurones. Nature, 321(6069): 519–522
MacDonald M E, et al, and the The Huntington’s Disease Collaborative Research Group (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell, 72(6): 971–983
Man H Y, Wang Q, Lu W Y, Ju W, Ahmadian G, Liu L, D’Souza S, Wong T P, Taghibiglou C, Lu J, Becker L E, Pei L, Liu F, Wymann M P, MacDonald J F, Wang Y T (2003). Activation of PI3-kinase is required for AMPA receptor insertion during LTP of mEPSCs in cultured hippocampal neurons. Neuron, 38(4): 611–624
Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, Lawton M, Trottier Y, Lehrach H, Davies S W, Bates G P (1996). Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell, 87(3): 493–506
Marklund N, Bakshi A, Castelbuono D J, Conte V, McIntosh T K (2006). Evaluation of pharmacological treatment strategies in traumatic brain injury. Curr Pharm Des, 12(13): 1645–1680
Martel M A, Ryan T J, Bell K F, Fowler J H, McMahon A, Al-Mubarak B, Komiyama N H, Horsburgh K, Kind P C, Grant S G, Wyllie D J, Hardingham G E (2012). The subtype of GluN2 C-terminal domain determines the response to excitotoxic insults. Neuron, 74(3): 543–556
Martel M A, Wyllie D J A, Hardingham G E (2009). In developing hippocampal neurons, NR2B-containing N-methyl-D-aspartate receptors (NMDARs) can mediate signaling to neuronal survival and synaptic potentiation, as well as neuronal death. Neuroscience, 158(1): 334–343
Martin H G S, Wang Y T (2010). Blocking the deadly effects of the NMDA receptor in stroke. Cell, 140(2): 174–176
Matsumoto T, Obrenovitch T P, Parkinson N A, Symon L (1990). Cortical activity, ionic homeostasis, and acidosis during rat brain repetitive ischemia. Stroke, 21(8): 1192–1198
Mattison H A, Hayashi T, Barria A (2012). Palmitoylation at two cysteine clusters on the C-terminus of GluN2A and GluN2B differentially control synaptic targeting of NMDA receptors. PLoS One, 7 (11): e49089
Mayer M L, Westbrook G L, Guthrie P B (1984). Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature, 309(5965): 261–263
McGeer E G, McGeer P L (1976). Duplication of biochemical changes of Huntington’s chorea by intrastriatal injections of glutamic and kainic acids. Nature, 263(5577): 517–519
Miller B R, Dorner J L, Shou M, Sari Y, Barton S J, Sengelaub D R, Kennedy R T, Rebec G V (2008). Up-regulation of GLT1 expression increases glutamate uptake and attenuates the Huntington’s disease phenotype in the R6/2 mouse. Neuroscience, 153(1): 329–337
Milnerwood A J, Cummings DM, Dallérac GM, Brown J Y, Vatsavayai S C, Hirst M C, Rezaie P, Murphy K P (2006). Early development of aberrant synaptic plasticity in a mouse model of Huntington’s disease. Hum Mol Genet, 15(10): 1690–1703
Milnerwood A J, Gladding C M, Pouladi M A, Kaufman A M, Hines R M, Boyd J D, Ko R W, Vasuta O C, Graham R K, Hayden M R, Murphy T H, Raymond L A (2010). Early increase in extrasynaptic NMDA receptor signaling and expression contributes to phenotype onset in Huntington’s disease mice. Neuron, 65(2): 178–190
Milnerwood A J, Kaufman A M, Sepers M D, Gladding C M, Zhang L, Wang L, Fan J, Coquinco A, Qiao J Y, Lee H, Wang Y T, Cynader M, Raymond L A (2012). Mitigation of augmented extrasynaptic NMDAR signaling and apoptosis in cortico-striatal co-cultures from Huntington's disease mice. Neurobiol Dis, 48(1): 40–51
Milnerwood A J, Raymond L A (2007). Corticostriatal synaptic function in mouse models of Huntington’s disease: early effects of huntingtin repeat length and protein load. J Physiol, 585 (Pt 3): 817–831
Minnerup J, Sutherland B A, Buchan A M, Kleinschnitz C (2012). Neuroprotection for stroke: current status and future perspectives. Int J Mol Sci, 13(9): 11753–11772
Monyer H, Sprengel R, Schoepfer R, Herb A, Higuchi M, Lomeli H, Burnashev N, Sakmann B, Seeburg P H (1992). Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science, 256(5060): 1217–1221
Mori H, Mishina M (1996). Molecular diversity and physiological roles of the NMDA-receptor channel. Nihon Yakurigaku Zasshi, 108(1): 1–12
Moriyoshi K, Masu M, Ishii T, Shigemoto R, Mizuno N, Nakanishi S (1991). Molecular cloning and characterization of the rat NMDA receptor. Nature, 354(6348): 31–37
Murphy K P, Carter R J, Lione L A, Mangiarini L, Mahal A, Bates G P, Dunnett S B, Morton A J (2000). Abnormal synaptic plasticity and impaired spatial cognition in mice transgenic for exon 1 of the human Huntington’s disease mutation. J Neurosci, 20(13): 5115–5123
O’Donnell L A, Agrawal A, Jordan-Sciutto K L, Dichter M A, Lynch D R, Kolson D L (2006). Human immunodeficiency virus (HIV)- induced neurotoxicity: roles for the NMDA receptor subtypes. J Neurosci, 26(3): 981–990
Obrenovitch T P, Urenjak J (1997). Is high extracellular glutamate the key to excitotoxicity in traumatic brain injury? J Neurotrauma, 14(10): 677–698
Okamoto S, Pouladi M A, Talantova M, Yao D, Xia P, Ehrnhoefer D E, Zaidi R, Clemente A, Kaul M, Graham R K, Zhang D, Vincent Chen H S, Tong G, Hayden M R, Lipton S A (2009). Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nat Med, 15(12): 1407–1413
Olney JW, Sharpe L G (1969). Brain lesions in an infant rhesus monkey treated with monsodium glutamate. Science, 166(3903): 386–388
Papadia S, Stevenson P, Hardingham N R, Bading H, Hardingham G E (2005). Nuclear Ca2+ and the cAMP response element-binding protein family mediate a late phase of activity-dependent neuroprotection. J Neurosci, 25(17): 4279–4287
Papouin T, Ladépêche L, Ruel J, Sacchi S, Labasque M, Hanini M, Groc L, Pollegioni L, Mothet J P, Oliet S H (2012). Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists. Cell, 150(3): 633–646
Parsons M P, Raymond L A (2014). Extrasynaptic NMDA receptor involvement in central nervous system disorders. Neuron, 82(2): 279–293
Parsons MP, Vanni MP, Woodard C L, Kang R, Murphy T H, Raymond L A (2016). Real-time imaging of glutamate clearance reveals normal striatal uptake in Huntington disease mouse models. Nat Commun, 7: 11251
Patrick G N, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai L H (1999). Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature, 402(6762): 615–622
Paul S, Nairn A C, Wang P, Lombroso P J (2003). NMDA-mediated activation of the tyrosine phosphatase STEP regulates the duration of ERK signaling. Nat Neurosci, 6(1): 34–42
Petralia R S, Wang Y X, Hua F, Yi Z, Zhou A, Ge L, Stephenson F A, Wenthold R J (2010). Organization of NMDA receptors at extrasynaptic locations. Neuroscience, 167(1): 68–87
Pop C, Salvesen G S (2009). Human caspases: activation, specificity, and regulation. J Biol Chem, 284(33): 21777–21781
Pouladi MA, Graham R K, Karasinska JM, Xie Y, Santos R D, Petersén A, Hayden M R (2009). Prevention of depressive behaviour in the YAC128 mouse model of Huntington disease by mutation at residue 586 of huntingtin. Brain, 132 (Pt 4): 919–932
Prybylowski K, Chang K, Sans N, Kan L, Vicini S, Wenthold R J (2005). The synaptic localization of NR2B-containing NMDA receptors is controlled by interactions with PDZ proteins and AP-2. Neuron, 47(6): 845–857
Rami A, Krieglstein J (1993). Protective effects of calpain inhibitors against neuronal damage caused by cytotoxic hypoxia in vitro and ischemia in vivo. Brain Res, 609 (1-2): 67–70
Rosas H D, Koroshetz W J, Chen Y I, Skeuse C, Vangel M, Cudkowicz M E, Caplan K, Marek K, Seidman L J, Makris N, Jenkins B G, Goldstein J M (2003). Evidence for more widespread cerebral pathology in early HD: an MRI-based morphometric analysis. Neurology, 60(10): 1615–1620
Rosenmund C, Clements J D, Westbrook G L (1993). Nonuniform probability of glutamate release at a hippocampal synapse. Science, 262(5134): 754–757
Saavedra A, Giralt A, Rué L, Xifró X, Xu J, Ortega Z, Lucas J J, Lombroso P J, Alberch J, Pérez-Navarro E (2011). Striatal-enriched protein tyrosine phosphatase expression and activity in Huntington’s disease: a STEP in the resistance to excitotoxicity. J Neurosci, 31(22): 8150–8162
Sanberg P R, Calderon S F, Giordano M, Tew J M, Norman A B (1989). The quinolinic acid model of Huntington’s disease: locomotor abnormalities. Exp Neurol, 105(1): 45–53
Sanberg P R, Lehmann J, Fibiger H C (1978). Impaired learning and memory after kainic acid lesions of the striatum: a behavioral model of Huntington’s disease. Brain Res, 149(2): 549–551
Sánchez I, Xu C J, Juo P, Kakizaka A, Blenis J, Yuan J (1999). Caspase-8 is required for cell death induced by expanded polyglutamine repeats. Neuron, 22(3): 623–633
Sanders S, Hayden M (2015). Aberrant palmitoylation in Huntington disease. BiochmSoc Trans, 43(2): 205–210
Sanz-Clemente A, Nicoll R A, Roche K W (2013). Diversity in NMDA receptor composition: many regulators, many consequences. Neuroscientist, 19(1): 62–75
Sattler R, Tymianski M (2000). Molecular mechanisms of calciumdependent excitotoxicity. J Mol Med (Berl), 78(1): 3–13
Sattler R, Xiong Z, Lu W Y, Hafner M, MacDonald J F, Tymianski M (1999). Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science, 284(5421): 1845–1848
Sawa A, Wiegand G W, Cooper J, Margolis R L, Sharp A H, Lawler J F, Greenamyre J T, Snyder S H, Ross C A (1999). Increased apoptosis of Huntington disease lymphoblasts associated with repeat length-dependent mitochondrial depolarization. Nat Med, 5(10): 1194–1198
Schwarcz R, Bennett J P, Coyle J T Jr (1977). Loss of striatal serotonin synaptic receptor binding induced by kainic acid lesions: correlations with Huntington’s Disease. J Neurochem, 28(4): 867–869
Shehadeh J, Fernandes H B, Zeron Mullins MM, Graham R K, Leavitt B R, Hayden M R, Raymond L A (2006). Striatal neuronal apoptosis is preferentially enhanced by NMDA receptor activation in YAC transgenic mouse model of Huntington disease. Neurobiol Dis, 21(2): 392–403
Sheng M, Cummings J, Roldan L A, Jan Y N, Jan L Y (1994). Changing subunit composition of heteromeric NMDA receptors during development of rat cortex. Nature, 368(6467): 144–147
Shirasaki D I, Greiner E R, Al-Ramahi I, Gray M, Boontheung P, Geschwind D H, Botas J, Coppola G, Horvath S, Loo J A, Yang XW (2012). Network organization of the huntingtin proteomic interactome in mammalian brain. Neuron, 75(1): 41–57
Siman R, Noszek J C (1988). Excitatory amino acids activate calpain I and induce structural protein breakdown in vivo. Neuron, 1(4): 279–287
Singaraja R R, Hadano S, Metzler M, Givan S, Wellington C L, Warby S, Yanai A, Gutekunst C A, Leavitt B R, Yi H, Fichter K, Gan L, McCutcheon K, Chopra V, Michel J, Hersch S M, Ikeda J E, Hayden MR (2002). HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis. Hum Mol Genet, 11(23): 2815–2828
Singaraja R R, Huang K, Sanders S S, Milnerwood A J, Hines R, Lerch J P, Franciosi S, Drisdel R C, Vaid K, Young F B, Doty C, Wan J, Bissada N, Henkelman R M, Green W N, Davis N G, Raymond L A, Hayden M R (2011). Altered palmitoylation and neuropathological deficits in mice lacking HIP14. Hum Mol Genet, 20(20): 3899–3909
Spargo E, Everall I P, Lantos P L (1993). Neuronal loss in the hippocampus in Huntington’s disease: a comparison with HIV infection. J Neurol Neurosurg Psychiatry, 56(5): 487–491
Sprengel R, Suchanek B, Amico C, Brusa R, Burnashev N, Rozov A, Hvalby O, Jensen V, Paulsen O, Andersen P, Kim J J, Thompson R F, Sun W, Webster L C, Grant S G, Eilers J, Konnerth A, Li J, McNamara J O, Seeburg P H (1998). Importance of the intracellular domain of NR2 subunits for NMDA receptor function in vivo. Cell, 92(2): 279–289
Strand A D, Baquet Z C, Aragaki A K, Holmans P, Yang L, Cleren C, Beal M F, Jones L, Kooperberg C, Olson J M, Jones K R (2007). Expression profiling of Huntington’s disease models suggests that brain-derived neurotrophic factor depletion plays a major role in striatal degeneration. J Neurosci, 27(43): 11758–11768
Sun Y, Savanenin A, Reddy P H, Liu Y F (2001). Polyglutamineexpanded huntingtin promotes sensitization of N-methyl-D-aspartate receptors via post-synaptic density 95. J Biol Chem, 276(27): 24713–24718
Sun Z, Del Mar N, Meade C, Goldowitz D, Reiner A (2002). Differential changes in striatal projection neurons in R6/2 transgenic mice for Huntington’s disease. Neurobiol Dis, 11(3): 369–385
Sutton L M, Sanders S S, Butland S L, Singaraja R R, Franciosi S, Southwell A L, Doty C N, SchmidtME, Mui K K, Kovalik V, Young F B, Zhang W, Hayden M R (2013). Hip14l-deficient mice develop neuropathological and behavioural features of Huntington disease. Hum Mol Genet, 22(3): 452–465
Tabrizi S J, Workman J, Hart P E, Mangiarini L, Mahal A, Bates G, Cooper J M, Schapira A H (2000). Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse. Ann Neurol, 47(1): 80–86
Tallaksen-Greene S J, Janiszewska A, Benton K, Ruprecht L, Albin R L (2010). Lack of efficacy of NMDA receptor-NR2B selective antagonists in the R6/2 model of Huntington disease. Exp Neurol, 225(2): 402–407
Tang T S, Slow E, Lupu V, Stavrovskaya I G, Sugimori M, Llinás R, Kristal B S, Hayden M R, Bezprozvanny I (2005). Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington’s disease. Proc Natl Acad Sci U S A, 102(7): 2602–2607
Terasaki Y, Sasaki T, Yagita Y, Okazaki S, Sugiyama Y, Oyama N, Omura-Matsuoka E, Sakoda S, Kitagawa K (2010). Activation of NR2A receptors induces ischemic tolerance through CREB signaling. J Cereb Blood Flow Metab, 30(8): 1441–1449
The Huntington’s Disease Collaborative Research Group (1993). A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell, 72(6): 971–983
Thomas C G, Miller A J, Westbrook G L (2006). Synaptic and extrasynaptic NMDA receptor NR2 subunits in cultured hippocampal neurons. J Neurophysiol, 95(3): 1727–1734
Tobin A J (2004). G. Bates, P. Harper, L. Jones (eds). Huntington’S disease, Third edition. Human Genet, 114(3): 320–321
Tovar K R, McGinley M J, Westbrook G L (2013). Triheteromeric NMDA receptors at hippocampal synapses. J Neurosci, 33(21): 9150–9160
Tovar K R, Westbrook G L (1999). The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro. J Neurosci, 19(10): 4180–4188
Tu W, Xu X, Peng L, Zhong X, Zhang W, Soundarapandian M M, Balel C, Wang M, Jia N, Zhang W, Lew F, Chan S L, Chen Y, Lu Y (2010). DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke. Cell, 140(2): 222–234
Tymianski M (2004). Stroke in 2013: Disappointments and advances in acute stroke intervention. Nat Rev Neurol, 10(2): 66–68
Uribe V, Wong B K, Graham R K, Cusack C L, Skotte N H, Pouladi M A, Xie Y, Feinberg K, Ou Y, Ouyang Y, Deng Y, Franciosi S, Bissada N, Spreeuw A, Zhang W, Ehrnhoefer D E, Vaid K, Miller F D, Deshmukh M, Howland D, Hayden M R (2012). Rescue from excitotoxicity and axonal degeneration accompanied by agedependent behavioral and neuroanatomical alterations in caspase-6- deficient mice. Hum Mol Genet, 21(9): 1954–1967
Usdin M T, Shelbourne P F, Myers R M, Madison D V (1999). Impaired synaptic plasticity in mice carrying the Huntington’s disease mutation. Hum Mol Genet, 8(5): 839–846
Van Raamsdonk J M, Pearson J, Slow E J, Hossain S M, Leavitt B R, HaydenMR (2005). Cognitive dysfunction precedes neuropathology and motor abnormalities in the YAC128 mouse model of Huntington’s disease. J Neurosci, 25(16): 4169–4180
Vonsattel J P, Myers R H, Stevens T J, Ferrante R J, Bird E D, Richardson E P (1985). Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol, 44(6): 559–577
Wang C X, Shuaib A (2005). NMDA/NR2B selective antagonists in the treatment of ischemic brain injury. Curr Drug Targets CNS Neurol Disord, 4(2): 143–151
Wang Y, Briz V, Chishti A, Bi X, Baudry M (2013). Distinct roles for mcalpain and m-calpain in synaptic NMDAR-mediated neuroprotection and extrasynaptic NMDAR-mediated neurodegeneration. J Neurosci, 33(48): 18880–18892
Warby S C, Doty C N, Graham R K, Carroll J B, Yang Y Z, Singaraja R R, Overall C M, Hayden M R (2008). Activated caspase-6 and caspase-6-cleaved fragments of huntingtin specifically colocalize in the nucleus. Hum Mol Genet, 17(15): 2390–2404
Watkins J C, Evans R H (1981). Excitatory amino acid transmitters. Annu Rev Pharmacol Toxicol, 21(1): 165–204
Wellington C, Ellerby LM, Gutekunst C A, Rogers D, Warby S, Graham R K, Loubser O, Van Raamsdonk J, Singaraja R, Yang Y Z, Gafni J, Bredesen D, Hersch S M, Leavitt B R, Roy S, Nicholson D W, Hayden M R (2002). Caspase cleavage of mutant Huntingtin precedes Neurodegeneration in Huntington’s disease. J Neurosci, 22(18): 7862–7872
Wellington C L, Ellerby L M, Hackam A S, Margolis R L, Trifiro M A, Singaraja R, McCutcheon K, Salvesen G S, Propp S S, Bromm M, Rowland K J, Zhang T, Rasper D, Roy S, Thornberry N, Pinsky L, Kakizuka A, Ross C A, Nicholson DW, Bredesen D E, Hayden M R (1998). Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J Biol Chem, 273(15): 9158–9167
Wellington C L, Singaraja R, Ellerby L, Savill J, Roy S, Leavitt B, Cattaneo E, Hackam A, Sharp A, Thornberry N, Nicholson D W, Bredesen D E, Hayden M R (2000). Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells. J Biol Chem, 275(26): 19831–19838
Williams K (1993). Ifenprodil discriminates subtypes of the N-methyl- D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. Mol Pharmacol, 44(4): 851–859
Wong B K Y, Ehrnhoefer D E, Graham R K, Martin D D, Ladha S, Uribe V, Stanek L M, Franciosi S, Qiu X, Deng Y, Kovalik V, Zhang W, PouladiMA, Shihabuddin L S, HaydenMR (2015). Partial rescue of some features of Huntington Disease in the genetic absence of caspase-6 in YAC128 mice. Neurobiol Dis, 76: 24–36
Wroge C M, Hogins J, Eisenman L, Mennerick S (2012). Synaptic NMDA receptors mediate hypoxic excitotoxic death. J Neurosci, 32(19): 6732–6742
Xia P, Chen H S, Zhang D, Lipton S A (2010). Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses. J Neurosci, 30(33): 11246–11250
Xu J, Kurup P, Zhang Y, Goebel-Goody S M, Wu P H, Hawasli A H, Baum M L, Bibb J A, Lombroso P J (2009). Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP. J Neurosci, 29(29): 9330–9343
Yamazaki M, Mori H, Araki K, Mori K J, Mishina M (1992). Cloning, expression and modulation of a mouse NMDA receptor subunit. FEBS Lett, 300(1): 39–45
Yan G M, Ni B, Weller M, Wood K A, Paul S M (1994). Depolarization or glutamate receptor activation blocks apoptotic cell death of cultured cerebellar granule neurons. Brain Res, 656(1): 43–51
Young A B, Greenamyre J T, Hollingsworth Z, Albin R, D’ Amato C, Shoulson I, Penney J B (1988). NMDA receptor losses in putamen from patients with Huntington’s disease. Science, 241(4868): 981–983
Young F B, Butland S L, Sanders S S, Sutton L M, Hayden M R (2012). Putting proteins in their place: Palmitoylation in Huntington disease and other neuropsychiatric diseases. Prog Neurobiol, 97(2): 220–238
Yuan H, Myers S J, Wells G, Nicholson K L, Swanger S A, Lyuboslavsky P, Tahirovic Y A, Menaldino D S, Ganesh T, Wilson L J, Liotta D C, Snyder J P, Traynelis S F (2015). Context-dependent GluN2B-selective inhibitors of NMDA receptor function are neuroprotective with minimal side effects. Neuron, 85(6): 1305–1318
Zeron M M, Hansson O, Chen N, Wellington C L, Leavitt B R, Brundin P, Hayden M R, Raymond L A (2002). Increased sensitivity to Nmethyl- D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington’s disease. Neuron, 33(6): 849–860
Zeron M M, Fernandes H B, Krebs C, Shehadeh J, Wellington C L, Leavitt B R, Baimbridge K G, Hayden M R, Raymond L A (2004). Potentiation of NMDA receptor-mediated excitotoxicity linked with intrinsic apoptotic pathway in YAC transgenic mouse model of Huntington’s disease. Mol Cell Neurosci, 25(3): 469–479
Zhang Q G, Wu D N, Han D, Zhang G Y (2007). Critical role of PTEN in the coupling between PI3K/Akt and JNK1/2 signaling in ischemic brain injury. FEBS Lett, 581(3): 495–505
Zhang S, Taghibiglou C, Girling K, Dong Z, Lin S Z, Lee W, ShyuWC, Wang Y T (2013). Critical role of increased PTEN nuclear translocation in excitotoxic and ischemic neuronal injuries. J Neurosci, 33(18): 7997–8008
Zhang S J, Steijaert M N, Lau D, Schtz G, Delucinge-Vivier C, Descombes P, Bading H (2007). Decoding NMDA receptor signaling: identification of genomic programs specifying neuronal survival and death. Neuron, 53(4): 549–562
Zhou L, Li F, Xu H B, Luo C X, Wu H Y, Zhu MM, Lu W, Ji X, Zhou Q G, Zhu D Y (2010). Treatment of cerebral ischemia by disrupting ischemia-induced interaction of nNOS with PSD-95. Nat Med, 16(12): 1439–1443
Zhou M, Baudry M (2006). Developmental changes in NMDA neurotoxicity reflect developmental changes in subunit composition of NMDA receptors. J Neurosci, 26(11): 2956–2963
Zhou X, Ding Q, Chen Z, Yun H, Wang H (2013). Involvement of the GluN2A and GluN2B subunits in synaptic and extrasynaptic Nmethyl- D-aspartate receptor function and neuronal excitotoxicity. J Biol Chem, 288(33): 24151–24159
Zuccato C, Valenza M, Cattaneo E (2010). Molecular mechanisms and potential therapeutical targets in Huntington’s disease. Physiol Rev, 90(3): 905–981
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Girling, K.D., Wang, Y.T. Neuroprotective strategies for NMDAR-mediated excitotoxicity in Huntington’s Disease. Front. Biol. 11, 439–458 (2016). https://doi.org/10.1007/s11515-016-1425-z
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DOI: https://doi.org/10.1007/s11515-016-1425-z