Neuroprotective strategies for NMDAR-mediated excitotoxicity in Huntington’s Disease

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 cell-survival 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.

Keywords

Huntington’s Disease / NMDA receptor / excitotoxicity / cell death / therapeutics

References

[1] 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

[2] 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

[3] Abiltrub M, Shattock M ( 2013). Cardiac dysautonomia in Huntington’s disease. J Huntington Dis, 2(3): 251–261

[4] 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

[5] Albin R L, Young A B, Penney J B, Handelin B, Balfour R, Anderson K D, Markel D S, Tourtellotte W W, 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

[6] 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

[7] 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

[8] 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

[9] 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

[10] Balázs R, Hack N, Jørgensen O S, Cotman C W (1989). N-methyl-D-aspartate promotes the survival of cerebellar granule cells: pharmacological characterization. Neurosci Lett, 101(3): 241–246

[11] 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

[12] 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

[13] Beal M F (1998). Excitotoxicity and nitric oxide in Parkinson’s disease pathogenesis. Ann Neurol, 44(3 Suppl 1): S110–S114

[14] Beal M F, Kowall N W, Ellison D W, Mazurek M F, Swartz K J, Martin J B (1986). Replication of the neurochemical characteristics of Huntington’s disease by quinolinic acid. Nature, 321(6066): 168–171

[15] Beighton P, Hayden M R (1981). Huntington’s chorea. S Afr Med J, 59(8): 250

[16] 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

[17] 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

[18] Bliss T V P, Collingridge G L (1993). A synaptic model of memory: long-term potentiation in the hippocampus. Nature, 361(6407): 31–39

[19] 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

[20] 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

[21] 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

[23] 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

[24] Burns L H, Pakzaban P, Deacon T W, 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

[22] 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

[25] Cepeda C, Hurst R S, Calvert C R, Hern�ndez-Echeagaray E, Nguyen O K, Jocoy E, Christian L J, Ariano M A, Levine M S (2003). Transient and progressive electrophysiological alterations in the corticostriatal pathway in a mouse model of Huntington’s disease. J Neurosci, 23(3): 961–969

[26] 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

[27] 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

[28] 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

[29] 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 R M (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

[30] Chen N, Luo T, Wellington C, Metzler M, McCutcheon K, Hayden M R, Raymond L A (1999). Subtype-specific enhancement of NMDA receptor currents by mutant huntingtin. J Neurochem, 72(5): 1890–1898

[31] Choi D W (1995). Calcium: still center-stage in hypoxic-ischemic neuronal death. Trends Neurosci, 18(2): 58–60

[32] 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

[33] Clements J D, Westbrook G L (1991). Activation kinetics reveal the number of glutamate and glycine binding sites on the N-methyl-D-aspartate receptor. Neuron, 7(4): 605–613

[46] 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

[34] 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

[35] 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

[36] 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

[37] 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

[38] Cull-Candy S, Brickley S, Farrant M (2001). NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol, 11(3): 327–335

[39] Cull-Candy S G, Leszkiewicz D N (2004). Role of distinct NMDA receptor subtypes at central synapses. Sci STKE, 2004(255): re16

[40] 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

[41] DeRidder 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

[42] 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

[43] DiFiglia M (1990). Excitotoxic injury of the neostriatum: a model for Huntington’s disease. Trends Neurosci, 13(7): 286–289

[44] Dingledine R, Borges K, Bowie D, Traynelis S F (1999). The glutamate receptor ion channels. Pharmacol Rev, 51(1): 7–61

[45] 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

[47] 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

[48] 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

[49] 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

[50] 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

[51] 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

[52] 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

[53] 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

[55] Ferrante R J, Kowall N W, Beal M F, Martin J B, Bird E D, Richardson E P Jr (1987). Morphologic and histochemical characteristics of a spared subset of striatal neurons in Huntington’s disease. J Neuropathol Exp Neurol, 46(1): 12–27

[56] 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

[57] Fischer G, Mutel V, Trube G, Malherbe P, Kew J N, Mohacsi E, Heitz M 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

[58] 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

[59] 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

[60] 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

[61] 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

[62] Friedman L K (2006). Calcium: a role for neuroprotection and sustained adaptation. Mol Interv, 6(6): 315–329

[63] Gafni J, Ellerby L M (2002). Calpain activation in Huntington’s disease. J Neurosci, 22(12): 4842–4849

[64] Gallagher M J, Huang H, Pritchett D B, Lynch D R (1996). Interactions between ifenprodil and the NR2B subunit of the N-methyl-D-aspartate receptor. J Biol Chem, 271(16): 9603–9611

[65] 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

[54] 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

[66] Gladding C M, Raymond L A (2011). Mechanisms underlying NMDA receptor synaptic/extrasynaptic distribution and function. Mol Cell Neurosci, 48(4): 308–320

[67] 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

[68] Gotti B, Duverger D, Bertin J, Carter C, Dupont R, Frost J, Gaudilliere B, MacKenzie E T, Rousseau J, Scatton B, (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

[69] 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

[95] 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

[70] 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

[71] 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 D W, 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

[72] Graham R K, Ehrnhoefer D E, Hayden M R (2011). Caspase-6 and neurodegeneration. Trends Neurosci, 34(12): 646–656

[73] 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

[74] 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

[75] Graveland G A, Williams R S, DiFiglia M (1985). Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington’s disease. Science, 227(4688): 770–773

[76] 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

[237] 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

[77] 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

[78] 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

[79] 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

[80] 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

[81] 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

[82] 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

[83] Hardingham G E, Bading H (2003). The Yin and Yang of NMDA receptor signalling. Trends Neurosci, 26(2): 81–89

[84] Hardingham G E, Bading H (2010). Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci, 11(10): 682–696

[85] 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

[86] Harjes P, Wanker E E (2003). The hunt for huntingtin function: interaction partners tell many different stories. Trends Biochem Sci, 28(8): 425–433

[87] 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

[88] 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

[89] Hayashi T, Thomas G M, Huganir R L (2009). Dual palmitoylation of NR2 subunits regulates NMDA receptor trafficking. Neuron, 64(2): 213–226

[90] 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

[91] 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 H M, Hayden M R, 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

[92] 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 J M, 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

[93] Hodgson J G, Agopyan N, Gutekunst C A, Leavitt B R, LePiane 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

[94] 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

[96] Huang K, Kang M H, 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

[97] Huang K, Yanai A, Kang R, Arstikaitis P, Singaraja R R, Metzler M, Mullard A, Haigh B, Gauthier-Campbell C, Gutekunst C A, Hayden M R, 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

[98] 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

[99] 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

[100] Ishii T, Moriyoshi K, Sugihara H, Sakurada K, Kadotani H, Yokoi M, Akazawa C, Shigemoto R, Mizuno N, Masu M, (1993). Molecular characterization of the family of the N-methyl-D-aspartate receptor subunits. J Biol Chem, 268(4): 2836–2843

[101] 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

[102] Jarabek B R (2003). Regulation of proteins affecting NMDA receptor-induced excitotoxicity in a Huntington’s mouse model. Brain, 127(3): 505–516

[103] Johnson J W, Ascher P (1987). Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature, 325(6104): 529–531

[104] Johnston M V (2005). Excitotoxicity in perinatal brain injury. Brain Pathol, 15(3): 234–240

[105] 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

[106] Kandel E R, Schwartz J H, Jessell T M (1995). Essentials of Neural Science and Behavior. McGraw Hill Professional

[107] 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

[108] 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

[109] 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

[110] Kaufman A M, Milnerwood A J, Sepers M D, 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

[111] Kew J N, Trube G, Kemp J A (1996). A novel mechanism of activity-dependent NMDA receptor antagonism describes the effect of ifenprodil in rat cultured cortical neurones. J Physiol, 497(Pt 3): 761–772

[112] 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

[113] 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

[114] Koike T, Martin D P, Johnson E M Jr (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

[115] Kornau H C, Schenker L T, Kennedy M B, Seeburg P H (1995). Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science, 269(5231): 1737–1740

[116] 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

[117] 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

[118] 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

[120] Lai T W, Wang Y T (2010). Fashioning drugs for stroke. Nat Med, 16(12): 1376–1378

[121] Lai T W, Zhang S, Wang Y T (2014). Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog Neurobiol, 115: 157–188

[122] 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

[123] 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

[124] 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

[125] 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

[126] 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, Chesselet M F (1999). Enhanced sensitivity to N-methyl-D-aspartate receptor activation in transgenic and knockin mouse models of Huntington's disease. J Neurosci Res, 58(4):515–532

[127] 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, Chesselet M F (1999). Enhanced sensitivity to N-methyl-D-aspartate receptor activation in transgenic and knockin mouse models of Huntington’s disease. J Neurosci Res, 58(4): 515–532

[128] 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

[119] 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

[239] 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, DiFiglia M (2009). Mutant Huntingtin Impairs Vesicle Formation from Recycling Endosomes by Interfering with Rab11 Activity. Mol Cell Biol, 29(22): 6106–6116

[240] Li S, Jin M, Koeglsperger T, Shepardson N E, Shankar G M, Selkoe D J (2011). Soluble Aβ oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J Neurosci, 31(8): 6627–6638

[129] 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

[130] 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

[131] 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

[132] 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

[133] 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

[134] 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

[135] 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

[136] 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

[137] López-Menéndez C, Gascón S, Sobrado M, Vidaurre O G, Higuero A M, 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

[138] 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

[139] Lucas D R, Newhouse J P (1957). The toxic effect of sodium L-glutamate on the inner layers of the retina. AMA Arch Ophthalmol, 58(2): 193–201

[140] 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

[141] MacDonald M E, , 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

[142] 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

[143] 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

[144] 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

[145] 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

[146] 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

[147] Martin H G S, Wang Y T (2010). Blocking the deadly effects of the NMDA receptor in stroke. Cell, 140(2): 174–176

[148] 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

[149] 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

[150] 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

[151] 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

[154] 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

[155] Milnerwood A J, Cummings D M, Dallérac G M, 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

[156] 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

[153] 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

[157] 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

[158] 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

[159] 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

[160] Mori H,Mishina M (1996). Molecular diversity and physiological roles of the NMDA-receptor channel. Nihon Yakurigaku Zasshi, 108(1): 1–12

[161] 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

[162] 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

[163] 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

[164] Obrenovitch T P, Urenjak J (1997). Is high extracellular glutamate the key to excitotoxicity in traumatic brain injury? J Neurotrauma, 14(10): 677–698

[165] 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

[166] Olney J W, Sharpe L G (1969). Brain lesions in an infant rhesus monkey treated with monsodium glutamate. Science, 166(3903): 386–388

[167] 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

[168] 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

[169] Parsons M P, Raymond L A (2014). Extrasynaptic NMDA receptor involvement in central nervous system disorders. Neuron, 82(2): 279–293

[170] Parsons M P, Vanni M P, 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

[171] 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

[172] 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

[173] 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

[174] Pop C, Salvesen G S (2009). Human caspases: activation, specificity, and regulation. J Biol Chem, 284(33): 21777–21781

[175] Pouladi M A, Graham R K, Karasinska J M, 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

[176] 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

[177] 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

[178] 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

[179] Rosenmund C, Clements J D, Westbrook G L (1993). Nonuniform probability of glutamate release at a hippocampal synapse. Science, 262(5134): 754–757

[180] 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

[181] 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

[241] 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

[182] 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

[242] Sanders S, Hayden M (2015). Aberrant palmitoylation in Huntington disease. BiochmSoc Trans, 43(2): 205–210

[183] Sanz-Clemente A, Nicoll R A,Roche K W (2013). Diversity in NMDA receptor composition: many regulators, many consequences. Neuroscientist, 19(1): 62–75

[184] Sattler R, Tymianski M (2000). Molecular mechanisms of calcium-dependent excitotoxicity. J Mol Med (Berl), 78(1): 3–13

[185] 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

[186] Sawa A, Wiegand G W, Cooper J, Margolis R L, Sharp A H, Lawler J F Jr, 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

[187] Schwarcz R, Bennett J P Jr, 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

[188] Shehadeh J, Fernandes H B, Zeron Mullins M M, 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

[189] 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

[190] 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 X W (2012). Network organization of the huntingtin proteomic interactome in mammalian brain. Neuron, 75(1): 41–57

[191] Siman R, Noszek J C (1988). Excitatory amino acids activate calpain I and induce structural protein breakdown in vivo. Neuron, 1(4): 279–287

[192] 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 M R (2002). HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis. Hum Mol Genet, 11(23): 2815–2828

[193] 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

[194] 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

[195] 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

[196] 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

[197] Sun Y, Savanenin A, Reddy P H, Liu Y F (2001). Polyglutamine-expanded huntingtin promotes sensitization of N-methyl-D-aspartate receptors via post-synaptic density 95. J Biol Chem, 276(27): 24713–24718

[198] 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

[199] Sutton L M, Sanders S S, Butland S L, Singaraja R R, Franciosi S, Southwell A L, Doty C N, Schmidt M E, 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

[200] 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

[201] 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

[202] 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

[203] 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

[204] 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

[205] 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

[243] Tobin A J (2004). G. Bates, P. Harper, L. Jones (eds). Huntington’S disease, Third edition. Human Genet, 114(3): 320–321

[206] Tovar K R, McGinley M J, Westbrook G L (2013). Triheteromeric NMDA receptors at hippocampal synapses. J Neurosci, 33(21): 9150–9160

[207] 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

[208] 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

[245] Tymianski M (2004). Stroke in 2013: Disappointments and advances in acute stroke intervention. Nat Rev Neurol, 10(2): 66–68

[209] 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 age-dependent behavioral and neuroanatomical alterations in caspase-6-deficient mice. Hum Mol Genet, 21(9): 1954–1967

[210] 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

[212] Van Raamsdonk J M, Pearson J, Slow E J, Hossain S M, Leavitt B R, Hayden M R (2005). Cognitive dysfunction precedes neuropathology and motor abnormalities in the YAC128 mouse model of Huntington’s disease. J Neurosci, 25(16): 4169–4180

[213] Vonsattel J P, Myers R H, Stevens T J, Ferrante R J, Bird E D, Richardson E P Jr (1985). Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol, 44(6): 559–577

[214] 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

[215] Wang Y, Briz V, Chishti A, Bi X, Baudry M (2013). Distinct roles for m-calpain and m-calpain in synaptic NMDAR-mediated neuroprotection and extrasynaptic NMDAR-mediated neurodegeneration. J Neurosci, 33(48): 18880–18892

[216] 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

[217] Watkins J C, Evans R H (1981). Excitatory amino acid transmitters. Annu Rev Pharmacol Toxicol, 21(1): 165–204

[211] Wellington C, Ellerby L M, 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

[218] 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 D W, 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

[219] 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

[220] 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

[221] 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, Pouladi M A, Shihabuddin L S, Hayden M R (2015). Partial rescue of some features of Huntington Disease in the genetic absence of caspase-6 in YAC128 mice. Neurobiol Dis, 76: 24–36

[222] Wroge C M, Hogins J, Eisenman L, Mennerick S (2012). Synaptic NMDA receptors mediate hypoxic excitotoxic death. J Neurosci, 32(19): 6732–6742

[223] 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

[224] 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

[225] 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

[226] 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

[227] 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

[246] 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

[228] 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

[229] 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 N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington’s disease. Neuron, 33(6): 849–860

[247] 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

[230] 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

[231] Zhang S, Taghibiglou C, Girling K, Dong Z, Lin S Z, Lee W, Shyu W C, Wang Y T (2013). Critical role of increased PTEN nuclear translocation in excitotoxic and ischemic neuronal injuries. J Neurosci, 33(18): 7997–8008

[232] Zhang S J, Steijaert M N, Lau D, Sch�tz 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

[233] Zhou L, Li F, Xu H B, Luo C X, Wu H Y, Zhu M M, 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

[234] 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

[235] Zhou X, Ding Q, Chen Z, Yun H, Wang H (2013). Involvement of the GluN2A and GluN2B subunits in synaptic and extrasynaptic N-methyl-D-aspartate receptor function and neuronal excitotoxicity. J Biol Chem, 288(33): 24151–24159

[236] Zuccato C, Valenza M, Cattaneo E (2010). Molecular mechanisms and potential therapeutical targets in Huntington’s disease. Physiol Rev, 90(3): 905–981

Compliance with ethical guidelines

Kimberly Girling and Yu Tian Wang declared that they have no conflict of interest. All institutional and national guidelines for the care and use of laboratory animals were followed. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

RIGHTS & PERMISSIONS

2016 Higher Education Press and Springer-Verlag Berlin Heidelberg