Synaptic Dysfunction in Huntington’s Disease



Huntington’s disease (HD) is a progressive, inherited, neurodegenerative disorder characterised by movement abnormalities, cognitive impairments and emotional disturbance (Bates et al. 2002). The genetic mutation for HD is an unstable CAG repeat expansion in the HD gene (Huntington’s Disease Collaborative Research Group 1993). The HD gene codes for a protein named huntingtin, and the CAG repeat is translated to an expanded polyglutamine repeat in the disease protein. However, even though the genetic mutation was identified more than 15 years ago, it is still not known how it causes HD. Until recently, the prevailing hypothesis was that the clinical manifestations of HD were due to selective neuronal degeneration in the striatum and cortex. Nevertheless, there is a growing body of work supporting the idea that some of the earliest changes apparent in HD, in particular changes in personality, mood and cognitive performance, may arise as a consequence of ­synaptic dysfunction. Here, we discuss the idea that synaptic dysfunction (rather than frank cell loss) may underlie early symptoms in HD.


Axonal Transport Snare Complex Mutant Huntingtin Expand Polyglutamine Repeat Normal Huntingtin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Andre VM, Cepeda C, Venegas A et al (2006) Altered cortical glutamate receptor function in the R6/2 model of Huntington’s disease. J Neurophysiol 95:2108–2119PubMedCrossRefGoogle Scholar
  2. Andrews TC, Weeks RA, Turjanski N et al (1999) Huntington’s disease progression. PET and clinical observations. Brain 122:2353–2363PubMedCrossRefGoogle Scholar
  3. Antonini A, Leenders KL, Spiegel R et al (1996) Striatal glucose metabolism and dopamine D2 receptor binding in asymptomatic gene carriers and patients with Huntington’s disease. Brain 119:2085–2095PubMedCrossRefGoogle Scholar
  4. Barr AM, Hofmann CE, Phillips AG et al (2005) Prenatal ethanol exposure in rats decreases levels of complexin proteins in the frontal cortex. Alcohol Clin Exp Res 29:1915–1920PubMedCrossRefGoogle Scholar
  5. Basso M, Giraudo S, Corpillo D et al (2004) Proteome analysis of human substantia nigra in Parkinson’s disease. Proteomics 4:3943–3952PubMedCrossRefGoogle Scholar
  6. Bates G, Harper PS, Jones L (2002) Huntington’s disease (3rd Edn) Oxford University Press, OxfordGoogle Scholar
  7. Bence NF, Sampat RM, Kopito RR (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292:1552–1555PubMedCrossRefGoogle Scholar
  8. Bird ED, Iversen LL (1974) Huntington’s chorea: measurement of glutamic acid decarboxylase, choline acetyltransferase and dopamine in basal ganglia. Brain 97:457–472PubMedCrossRefGoogle Scholar
  9. Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39PubMedCrossRefGoogle Scholar
  10. Block-Galarza J, Chase KO, Sapp E et al (1997) Fast transport and retrograde movement of huntingtin and HAP 1 in axons. Neuroreport 8:2247–2251PubMedCrossRefGoogle Scholar
  11. Bowman AB, Yoo SY, Dantuma NP et al (2005) Neuronal dysfunction in a polyglutamine disease model occurs in the absence of ubiquitin-proteasome system impairment and inversely correlates with the degree of nuclear inclusion formation. Hum Mol Genet 14:679–691PubMedCrossRefGoogle Scholar
  12. Brandt J, Butters N (1986) The neuropsychology of Huntington’s disease. Trends Neurosci 9:118–120CrossRefGoogle Scholar
  13. Brose N (2008) Altered complexin expression in psychiatric and neurological disorders: cause or consequence? Mol Cells 25:7–19PubMedGoogle Scholar
  14. Butterworth MB, Frizzell RA, Johnson JP et al (2005) PKA-dependent ENaC trafficking requires the SNARE-binding protein complexin. Am J Physiol Renal Physiol 289:F969–F977PubMedCrossRefGoogle Scholar
  15. Cai H, Reim K, Varoqueaux F et al (2008) Complexin II plays a positive role in Ca2+-triggered exocytosis by facilitating vesicle priming. Proc Natl Acad Sci U S A 105:19538–19543PubMedCrossRefGoogle Scholar
  16. Carter RJ, Lione, LA, Humby T et al (1999) Characterisation of progressive motor deficits in mice transgenic for the Huntington’s disease mutation. J Neurosci 19:3248–3257PubMedGoogle Scholar
  17. Castro ME, Pascual J, Romon T et al (1998) 5-HT1B receptor binding in degenerative movement disorders. Brain Res 790:323–328PubMedCrossRefGoogle Scholar
  18. Cattaneo E, Zuccato C, Tartari M (2005) Normal huntingtin function: an alternative approach to Huntington’s disease. Nat Rev Neurosci 6:919–930PubMedCrossRefGoogle Scholar
  19. Cepeda C, Ariano MA, Calvert CR et al (2001) NMDA receptor function in mouse models of Huntington disease. J Neurosci Res 66:525–539PubMedCrossRefGoogle Scholar
  20. Cepeda C, Hurst RS, Calvert CR et al (2003) Transient and progressive electrophysiological alterations in the corticostriatal pathway in a mouse model of Huntington’s disease. J Neurosci 23:961–969PubMedGoogle Scholar
  21. Cepeda C, Wu N, Andre VM et al (2007) The corticostriatal pathway in Huntington’s disease. Prog Neurobiol 81:253–271PubMedCrossRefGoogle Scholar
  22. Cha JH, Kosinski CM, Kerner JA et al (1998) Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human huntington disease gene. Proc Natl Acad Sci U S A 95:6480–6485PubMedCrossRefGoogle Scholar
  23. Cha JH, Frey AS, Alsdorf SA et al (1999) Altered neurotransmitter receptor expression in transgenic mouse models of Huntington’s disease. Philos Trans R Soc Lond A 354:981–989CrossRefGoogle Scholar
  24. Chen X, Tomchick DR, Kovrigin E et al (2002) Three-dimensional structure of the complexin/SNARE complex. Neuron 33:397–409PubMedCrossRefGoogle Scholar
  25. Ciechanover A, Brundin P (2003) The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron 40:427–446PubMedCrossRefGoogle Scholar
  26. Cummings DM, Milnerwood AJ, Dallérac GM et al (2007) Abnormal cortical synaptic plasticity in a mouse model of Huntington’s disease. Brain Res Bull 72:103–107PubMedCrossRefGoogle Scholar
  27. Davies SW, Turmaine M, Cozens BA et al (1997) Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90:537–548PubMedCrossRefGoogle Scholar
  28. Davies S, Ramsden DB (2001) Huntington’s disease. Mol Pathol 54:409–413PubMedGoogle Scholar
  29. DiFiglia M, Sapp E, Chase K et al (1995) Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron 14:1075–1081PubMedCrossRefGoogle Scholar
  30. DiFiglia M, Sapp E, Chase KO et al (1997) Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277:1990–1993PubMedCrossRefGoogle Scholar
  31. DiProspero NA, Chen EY, Charles V et al (2004) Early changes in Huntington’s disease patient brains involve alterations in cytoskeletal and synaptic elements. J Neurocytol 33:517–533PubMedCrossRefGoogle Scholar
  32. Dompierre JP, Godin JD, Charrin BC et al (2007) Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington’s disease by increasing tubulin acetylation. J Neurosci 27:3571–3583PubMedCrossRefGoogle Scholar
  33. Drew CJ, Kyd RJ, Morton AJ (2007) Complexin 1 knockout mice exhibit marked deficits in social behaviours but appear to be cognitively normal. Hum Mol Genet 16:2288–2305PubMedCrossRefGoogle Scholar
  34. Dure LS 4th, Young AB, Penney JB (1991) Excitatory amino acid binding sites in the caudate nucleus and frontal cortex of Huntington’s disease. Ann Neurol 30:785–793PubMedCrossRefGoogle Scholar
  35. Eastwood SL, Harrison PJ (2000) Hippocampal synaptic pathology in schizophrenia, bipolar disorder and major depression: a study of complexin mRNAs. Mol Psychiatry 5:425–432PubMedCrossRefGoogle Scholar
  36. Eastwood, SL, Cotter D, Harrison PJ (2001) Cerebellar synaptic protein expression in schizophrenia. Neuroscience 105:219–229PubMedCrossRefGoogle Scholar
  37. Eastwood SL, Harrison PJ (2001) Synaptic pathology in the anterior cingulate cortex in schizophrenia and mood disorders. A review and a Western blot study of synaptophysin, GAP-43 and the complexins. Brain Res Bull 55:569–578PubMedCrossRefGoogle Scholar
  38. Eastwood SL (2004) The synaptic pathology of schizophrenia: is aberrant neurodevelopment and plasticity to blame? Int Rev Neurobiol 59:47–72PubMedCrossRefGoogle Scholar
  39. Eastwood SL, Harrison PJ (2005) Decreased expression of vesicular glutamate transporter 1 and complexin II mRNAs in schizophrenia: further evidence for a synaptic pathology affecting glutamate neurons. Schizophr Res 73:159–172PubMedCrossRefGoogle Scholar
  40. Edwardson JM, Wang CT, Gong B et al (2003) Expression of mutant huntingtin blocks exocytosis in PC12 cells by depletion of complexin II. J Biol Chem 278:30849–30853PubMedCrossRefGoogle Scholar
  41. Engelender S, Sharp AH, Colomer V et al (1997) Huntingtin-associated protein 1 (HAP1) interacts with the p150Glued subunit of dynactin. Hum Mol Genet 6:2205–2212PubMedCrossRefGoogle Scholar
  42. Engqvist-Goldstein AE, Kessels MM, Chopra VS et al (1999) An actin-binding protein of the Sla2/Huntingtin interacting protein 1 family is a novel component of clathrin-coated pits and vesicles. J Cell Biol 147:1503–1518PubMedCrossRefGoogle Scholar
  43. Fan MM, Raymond LA (2007) N-methyl-D-aspartate (NMDA) receptor function and excitotoxicity in Huntington’s disease. Prog Neurobiol 81:272–293PubMedCrossRefGoogle Scholar
  44. Faull RL, Waldvogel HJ, Nicholson LF et al (1993) The distribution of GABAA-benzodiazepine receptors in the basal ganglia in Huntington’s disease and in the quinolinic acid-lesioned rat. Prog Brain Res 99:105–123PubMedCrossRefGoogle Scholar
  45. Ferrante RJ, Kowall NW, Richardson EP Jr (1991) Proliferative and degenerative changes in striatal spiny neurons in Huntington’s disease: a combined study using the section-Golgi method and calbindin D28k immunocytochemistry. J Neurosci 11:3877–3887PubMedGoogle Scholar
  46. Fiebig KM, Rice LM, Pollack E et al (1999) Folding intermediates of SNARE complex assembly. Nat Struct Biol 6:117–123PubMedCrossRefGoogle Scholar
  47. Folstein SE, Jensen B, Leigh RJ et al (1983) The measurement of abnormal movement: methods developed for Huntington’s disease. Neurobehav Toxicol Teratol 5:605–609PubMedGoogle Scholar
  48. Freeman W, Morton AJ (2004a) Regional and progressive changes in brain expression of complexin II in a mouse transgenic for the Huntington’s Disease mutation. Brain Res Bull 63:45–55PubMedCrossRefGoogle Scholar
  49. Freeman W, Morton AJ (2004b) Differential messenger RNA expression of complexins in mouse brain. Brain Res Bull 63:33–44PubMedCrossRefGoogle Scholar
  50. Gibson HE, Reim K, Brose N et al (2005) A similar impairment in CA3 mossy fibre LTP in the R6/2 mouse model of Huntington’s disease and in the complexin II knockout mouse. Eur J Neurosci 22:1701–1712PubMedCrossRefGoogle Scholar
  51. Gil JM, Rego AC (2008) Mechanisms of neurodegeneration in Huntington’s disease. Eur J Neurosci 27:2803–2820PubMedCrossRefGoogle Scholar
  52. Giraudo CG, Eng WS, Melia TJ et al (2006) A clamping mechanism involved in SNARE-dependent exocytosis. Science 283:21211–21219Google Scholar
  53. Glass M, Faull RL, Dragunow M (1993) Loss of cannabinoid receptors in the substantia nigra in Huntington’s disease. Neuroscience 56:523–527PubMedCrossRefGoogle Scholar
  54. Glass M, Dragunow M, Faull RL (2000) The pattern of neurodegeneration in Huntington’s disease: a comparative study of cannabinoid, dopamine, adenosine and GABA(A) receptor alterations in the human basal ganglia in Huntington’s disease. Neuroscience 97:505–519PubMedCrossRefGoogle Scholar
  55. Glass M (2001) The role of cannabinoids in neurodegenerative diseases. Prog Neuropsychopharmacol Biol Psychiatry 25:743–765PubMedCrossRefGoogle Scholar
  56. Glynn D, Bortnick RA, Morton AJ (2003) Complexin II is essential for normal neurological function in mice. Hum Mol Genet 12:2431–3448PubMedCrossRefGoogle Scholar
  57. Glynn D, Drew CJ, Reim K et al (2005) Profound ataxia in Complexin 1 knockout mice masks a complex phenotype that includes exploratory and habituation deficits. Hum Mol Genet 14:2369–2385PubMedCrossRefGoogle Scholar
  58. Glynn D, Morton AJ (2006) Deficits in information processing and social behaviours in the Complexin 2 knockout mouse. FENS Abstract 3:A458Google Scholar
  59. Glynn D, Sizemore RJ, Morton AJ (2007a) Early motor development is abnormal in complexin 1 knockout mice. Neurobiol Dis 25:483–495PubMedCrossRefGoogle Scholar
  60. Glynn D, Reim K, Brose N et al (2007b) Depletion of Complexin II does not affect disease progression in a mouse model of Huntington’s disease (HD); support for role for complexin II in behavioural pathology in a mouse model of HD. Brain Res Bull 72:108–120PubMedCrossRefGoogle Scholar
  61. Graveland GA, Williams RS, DiFiglia M (1985) Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington’s disease. Science 227:770–773PubMedCrossRefGoogle Scholar
  62. Gray M, Shirasaki DI, Cepeda C et al (2008) Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J Neurosci 28:6182–6195PubMedCrossRefGoogle Scholar
  63. Gunawardena S, Her LS, Brusch RG et al (2003) Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron 40:25–40PubMedCrossRefGoogle Scholar
  64. Gunawardena S, Goldstein LS (2005) Polyglutamine diseases and transport problems: deadly traffic jams on neuronal highways. Arch Neurol 62:46–51PubMedCrossRefGoogle Scholar
  65. Hansson O, Guatteo E, Mercuri NB et al (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 14:1492–1504PubMedCrossRefGoogle Scholar
  66. Harrison PJ, Eastwood SL (1998) Preferential involvement of excitatory neurons in medial temporal lobe in schizophrenia. Lancet 352:1669–1673PubMedCrossRefGoogle Scholar
  67. Harrison PJ, Eastwood SL (2000) Hippocampal synaptic pathology in schizophrenia, bipolar disorder and major depression: a study of complexin mRNAs. Mol Psychiatry 5:425–532PubMedCrossRefGoogle Scholar
  68. Hartl FU, Hayer-Hartl M (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295:1852–1858PubMedCrossRefGoogle Scholar
  69. Hazell AS, Wang C (2005) Downregulation of complexin I and complexin II in the medial thalamus is blocked by N-acetylcysteine in experimental Wernicke’s encephalopathy. J Neurosci Res 79:200–207PubMedCrossRefGoogle Scholar
  70. Hedreen JC, Peyser CE, Folstein SE et al (1991) Neuronal loss in layers V and VI of cerebral cortex in Huntington’s disease. Neurosci Lett 133:257–261PubMedCrossRefGoogle Scholar
  71. Hershko A, Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67:425–479PubMedCrossRefGoogle Scholar
  72. Hilditch-Maguire P, Trettel F, Passani LA et al (2000) Huntingtin: an iron-regulated protein essential for normal nuclear and perinuclear organelles. Hum Mol Genet 9:2789–2797PubMedCrossRefGoogle Scholar
  73. Hiley CR, Bird ED (1974) Decreased muscarinic receptor concentration in post-mortem brain in Huntington’s chorea. Brain Res 80:355–358PubMedCrossRefGoogle Scholar
  74. Hodgson JG, Agopyan N, Gutekunst CA et al (1999) A YAC mouse model for Huntington’s disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 23:181–192PubMedCrossRefGoogle Scholar
  75. Holthoff VA, Koeppe RA, Frey KA et al (1993) Positron emission tomography measures of benzodiazepine receptors in Huntington’s disease. Ann Neurol 34:76–81PubMedCrossRefGoogle Scholar
  76. 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 72:971–983CrossRefGoogle Scholar
  77. Huntwork S, Littleton JT (2007) A complexin fusion clamp regulates spontaneous neurotransmitter release and synaptic growth. Nat Neurosci 10:1235–1237PubMedCrossRefGoogle Scholar
  78. Jahn R, Südhof TC (1999) Membrane fusion and exocytosis. Annu Rev Biochem 68:863–911PubMedCrossRefGoogle Scholar
  79. Jahn R, Scheller RH (2006) SNAREs-engines for membrane fusion. Nat Rev Mol Cell Biol 7:631–643PubMedCrossRefGoogle Scholar
  80. Jana NR, Zemskov EA, Wang GH et al (2001) Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release. Hum Mol Genet 10:1049–1059PubMedCrossRefGoogle Scholar
  81. Jason GW, Pajurkova EM, Suchowersky OEA (1988) Presymptomatic neuropsychological impairment in Huntington’s disease. Arch Neurol 45:769–773PubMedCrossRefGoogle Scholar
  82. Kalchman MA, Koide HB, McCutcheon K et al (1997) HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain. Nat Genet 16:44–53PubMedCrossRefGoogle Scholar
  83. Kittler JT, Thomas P, Tretter V et al (2004) Huntingtin-associated protein 1 regulates inhibitory synaptic transmission by modulating gamma-aminobutyric acid type A receptor membrane trafficking. Proc Natl Acad Sci U S A 101:12736–12741PubMedCrossRefGoogle Scholar
  84. Klapstein GJ, Fisher RS, Zanjani H et al (2001) Electrophysiological and morphological changes in striatal spiny neurons in R6/2 Huntington’s disease transgenic mice. J Neurophysiol 86:2667–2677PubMedGoogle Scholar
  85. Kremer HP, Roos RA, Dingjan G et al (1990) Atrophy of the hypothalamic lateral tuberal nucleus in Huntington’s disease. J Neuropathol Exp Neurol 49:371–382PubMedCrossRefGoogle Scholar
  86. Kung VW, Hassam R, Morton AJ, Jones S (2007) Neuroscience 146:1571–1580PubMedCrossRefGoogle Scholar
  87. Laforet GA, Sapp E, Chase K et al (2001) Changes in cortical and striatal neurons predict behavioral and electrophysiological abnormalities in a transgenic murine model of Huntington’s disease. J Neurosci 21:9112–9123PubMedGoogle Scholar
  88. Lastres-Becker I, Fezza F, Cebeira M et al (2001) Changes in endocannabinoid transmission in the basal ganglia in a rat model of Huntington’s disease. Neuroreport 12:2125–2129PubMedCrossRefGoogle Scholar
  89. Lastres-Becker I, Gomez M, De Miguel R et al (2002) Loss of cannabinoid CB(1) receptors in the basal ganglia in the late akinetic phase of rats with experimental Huntington’s disease. Neurotox Res 4:601–608PubMedCrossRefGoogle Scholar
  90. Lawrence AD, Sahakian BJ, Hodges JR et al (1996) Executive and mnemonic functions in early Huntington’s disease. Brain 119:1633–1645PubMedCrossRefGoogle Scholar
  91. Lawrence AD, Weeks RA, Brooks DJ et al (1998) The relationship between striatal dopamine receptor binding and cognitive performance in Huntington’s disease. Brain 121:1343–1355PubMedCrossRefGoogle Scholar
  92. Lawrence AD, Sahakian BJ, Rogers RD et al (1999) Discrimination, reversal, and shift learning in Huntington’s disease mechanisms of impaired response selection. Neuropsychologia 37:1359–1374PubMedCrossRefGoogle Scholar
  93. Lee WC, Yoshihara M, Littleton JT (2004) Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington’s disease. Proc Natl Acad Sci U S A 101:3224–3229PubMedCrossRefGoogle Scholar
  94. Legendre-Guillemin V, Metzler M, Charbonneau M et al (2002) HIP1 and HIP12 display differential binding to F-actin, AP2, and clathrin. Identification of a novel interaction with clathrin light chain. J Biol Chem 277:19897–19904PubMedCrossRefGoogle Scholar
  95. Levine MS, Klapstein GJ, Koppel A et al (1999) Enhanced sensitivity to N-methyl-D-aspartate receptor activation in transgenic and knockin mouse models of Huntington’s disease. J Neurosci Res 58:515–532PubMedCrossRefGoogle Scholar
  96. Li XJ, Li SH, Sharp AH et al (1995) A huntingtin-associated protein enriched in brain with i­mplications for pathology. Nature 378:398–402PubMedCrossRefGoogle Scholar
  97. Li SH, Gutekunst CA, Hersch SM et al (1998) Interaction of huntingtin-associated protein with dynactin P150Glued. J Neurosci 18:1261–1269PubMedGoogle Scholar
  98. Li H, Li SH, Yu ZX et al (2001) Huntingtin aggregate-associated axonal degeneration is an early pathological event in Huntington’s disease mice. J Neurosci 21:8473–8481PubMedGoogle Scholar
  99. Li Y, Chin LS, Levey AI et al (2002) Huntingtin-associated protein 1 interacts with hepatocyte growth factor-regulated tyrosine kinase substrate and functions in endosomal trafficking. J Biol Chem 277:28212–28221PubMedCrossRefGoogle Scholar
  100. Li JY, Plomann M, Brundin P (2003) Huntington’s disease: a synaptopathy? Trends Mol Med 9:414–420PubMedCrossRefGoogle Scholar
  101. Li L, Murphy TH, Hayden MR et al (2004) Enhanced striatal NR2B-containing N-methyl-D-aspartate receptor-mediated synaptic currents in a mouse model of Huntington disease. J Neurophysiol 92:2738–2746PubMedCrossRefGoogle Scholar
  102. Lievens JC, Woodman B, Mahal A et al (2001) Impaired glutamate uptake in the R6 Huntington’s disease transgenic mice. Neurobiol Dis 8:807–821PubMedCrossRefGoogle Scholar
  103. Lin RC, Scheller RH (2000) Mechanisms of synaptic vesicle exocytosis. Annu Rev Cell Dev Biol 16:1–49CrossRefGoogle Scholar
  104. Lione LA, Carter RJ, Hunt MJ et al (1999) Selective discrimination learning impairments in mice expressing the human Huntington’s disease mutation. J Neurosci 19:10428–10437PubMedGoogle Scholar
  105. London ED, Yamamura HI, Bird ED et al (1981) Decreased receptor-binding sites for kainic acid in brains of patients with Huntington’s disease. Biol Psychiatry 16:155–162PubMedGoogle Scholar
  106. Luthi-Carter R, Strand A, Peters NL et al (2000) Decreased expression of striatal signaling genes in a mouse model of Huntington’s disease. Hum Mol Genet 9:1259–1271PubMedCrossRefGoogle Scholar
  107. Lynch G, Kramar EA, Rex CS et al (2007) Brain-derived neurotrophic factor restores synaptic plasticity in a knock-in mouse model of Huntington’s disease. J Neurosci 27:4424–4434PubMedCrossRefGoogle Scholar
  108. Maccarrone M, Battista N, Centonze D (2007) The endocannabinoid pathway in Huntington’s disease: a comparison with other neurodegenerative diseases. Prog Neurobiol 81:349–379PubMedCrossRefGoogle Scholar
  109. Mangiarini L, Sathasivam K, Seller M et al (1996) Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87:493–506PubMedCrossRefGoogle Scholar
  110. Martinez-Mir MI, Probst A, Palacios JM (1991) Adenosine A2 receptors: selective localization in the human basal ganglia and alterations with disease. Neuroscience 3:697–706CrossRefGoogle Scholar
  111. Mazarakis NK, Cybulska-Klosowicz A, Grote H et al (2005) Deficits in experience-dependent cortical plasticity and sensory-discrimination learning in presymptomatic Huntington’s disease mice. J Neurosci 25:3059–3066PubMedCrossRefGoogle Scholar
  112. McCaw EA, Hu H, Gomez GT et al (2004) Structure, expression and regulation of the cannabinoid receptor gene (CB1) in Huntington’s disease transgenic mice. Eur J Biochem 271:4909–4920PubMedCrossRefGoogle Scholar
  113. McMahon HJ, Missler M, Li C et al (1995) Complexins: cytosolic proteins that regulate SNAP receptor function. Cell 83:111–119PubMedCrossRefGoogle Scholar
  114. Melia TJ Jr (2007) Putting the clamps on membrane fusion: how complexin sets the stage for calcium-mediated exocytosis. FEBS Lett 581:2131–2139PubMedCrossRefGoogle Scholar
  115. Menalled LB, Chesselet MF (2002) Mouse models of Huntington’s disease. Trends Pharmacol Sci 23:32–39PubMedCrossRefGoogle Scholar
  116. Menalled LB (2005) Knock-in mouse models of Huntington’s disease. NeuroRx 2:465–470PubMedCrossRefGoogle Scholar
  117. Metzler M, Li B, Gan L et al (2003) Disruption of the endocytic protein HIP1 results in neurological deficits and decreased AMPA receptor trafficking. EMBO J 22:3254–3266PubMedCrossRefGoogle Scholar
  118. Milnerwood AJ, Cummings DM, Dallerac GM et al (2006) Early development of aberrant synaptic plasticity in a mouse model of Huntington’s disease. Hum Mol Genet 15:1690–1703PubMedCrossRefGoogle Scholar
  119. Milnerwood AJ, Raymond LA (2007) Corticostriatal synaptic function in mouse models of Huntington’s disease: early effects of huntingtin repeat length and protein load. J Physiol 585:817–831PubMedCrossRefGoogle Scholar
  120. Mizuno H, Shibayama H, Tanaka F et al (2000) An autopsy case with clinically and molecular genetically diagnosed Huntington’s disease with only minimal non-specific neuropathological findings. Clin Neuropathol 19:94–103PubMedGoogle Scholar
  121. Modregger J, DiProspero NA, Charles V et al (2002) PACSIN 1 interacts with huntingtin and is absent from synaptic varicosities in presymptomatic Huntington’s disease brains. Hum Mol Genet 11:2547–2558PubMedCrossRefGoogle Scholar
  122. Modregger J, Schmidt AA, Ritter B et al (2003) Characterization of Endophilin B1b, a brain-specific membrane-associated lysophosphatidic acid acyl transferase with properties distinct from endophilin A1. J Biol Chem 278:4160–4167PubMedCrossRefGoogle Scholar
  123. Montoya A, Price BH, Menear M et al (2006) Brain imaging and cognitive dysfunctions in Huntington’s disease. J Psychiatry Neurosci 31:21–29PubMedGoogle Scholar
  124. Morfini GA, You YM, Pollema SL et al (2009) Pathogenic huntingtin inhibits fast axonal transport by activating JNK3 and phosphorylating kinesin. Nat Neurosci 12:864–871PubMedCrossRefGoogle Scholar
  125. Morton AJ, Lagan MA, Skepper JN et al (2000) Progressive formation of inclusions in the striatum and hippocampus of mice transgenic for the human Huntington’s disease mutation. J Neurocytol 29:679–702PubMedCrossRefGoogle Scholar
  126. Morton AJ, Edwardson JM (2001) Progressive depletion of CPLXII in a transgenic mouse model of Huntington’s disease. J Neurochem 76:166–172PubMedCrossRefGoogle Scholar
  127. Morton AJ, Faull RLM, Edwardson JM (2001) Abnormalities in the synaptic vesicle fusion machinery in Huntington’s disease. Brain Res Bull 56:111–117PubMedCrossRefGoogle Scholar
  128. Morton AJ, Hunt MJ, Hodges AK et al (2005) A combination drug therapy improves cognition and reverses gene expression changes in a mouse model of Huntington’s disease. Eur J Neurosci 21:855–870PubMedCrossRefGoogle Scholar
  129. Murphy KP, Carter RJ, Lione LA et al (2000) Abnormal synaptic plasticity and impaired spatial cognition in mice transgenic for exon 1 of the human Huntington’s disease mutation. J Neurosci 20:5115–5123PubMedGoogle Scholar
  130. Myers RH, Vonsattel JP, Stevens TJ et al (1988) Clinical and neuropathologic assessment of severity in Huntington’s disease. Neurology 38:341–347PubMedCrossRefGoogle Scholar
  131. Nicniocaill B, Haraldsson B, Hansson O et al (2001) Altered striatal amino acid neurotransmitter release monitored using microdialysis in R6/1 Huntington transgenic mice. Eur J Neurosci 13:206–210PubMedCrossRefGoogle Scholar
  132. Nithianantharajah, J, Barkus, C, Murphy, M et al (2008) Gene–environment interactions modulating cognitive function and molecular correlates of synaptic plasticity in Huntington’s disease transgenic mice. Neurobiol Dis 29:490–504PubMedCrossRefGoogle Scholar
  133. Ono S, Baux G, Sekiguchi M et al (1998) Regulatory roles of complexins in neurotransmitter release from mature presynaptic nerve terminals. Eur J Neurosci 10:2143–2152PubMedCrossRefGoogle Scholar
  134. Pabst S, Margittai M, Vainius D et al (2002) Rapid and selective binding to the synaptic SNARE complex suggests a modulatory role of complexins in neuroexocytosis. J Biol Chem 277:7838–7848PubMedCrossRefGoogle Scholar
  135. Pang, TY, Stam, NC, Nithianantharajah, J et al (2006) Differential effects of voluntary physical exercise on behavioural and brain-derived neurotrophic factor expression deficits in Huntington’s disease transgenic mice. Neuroscience 141:569–584PubMedCrossRefGoogle Scholar
  136. Patel S, Sinha A, Singh MP (2007) Identification of differentially expressed proteins in striatum of maneb-and paraquat-induced Parkinson’s disease phenotype in mouse. Neurotoxicol Teratol 29:578–585PubMedCrossRefGoogle Scholar
  137. Pavese N, Andrews TC, Brooks DJ et al (2003) Progressive striatal and cortical dopamine receptor dysfunction in Huntington’s disease: a PET study. Brain 126:1127–1135PubMedCrossRefGoogle Scholar
  138. Perry TL, Hansen S, Kloster M (1973) Huntington’s chorea: deficiency of gamma aminobutyric acid in brain. N Engl J Med 288:337–342PubMedCrossRefGoogle Scholar
  139. Petersen A, Puschban Z, Lotharius J et al (2002) Evidence for dysfunction of the nigrostriatal pathway in the R6/1 line of transgenic Huntington’s disease mice. Neurobiol Dis 11:134–146PubMedCrossRefGoogle Scholar
  140. Pisani A, Bernardi G, Ding J et al (2007) Re-emergence of striatal cholinergic interneurons in movement disorders. Trends Neurosci 30:545–553PubMedCrossRefGoogle Scholar
  141. Politis M, Pavese N, Tai YF et al (2008) Hypothalamic involvement in Huntington’s disease: an in vivo PET study. Brain 131:2860–2869PubMedCrossRefGoogle Scholar
  142. Reddy PH, Williams M, Tagle DA (1999) Recent advances in understanding the pathogenesis of Huntington’s disease. Trends Neurosci 22:248–255PubMedCrossRefGoogle Scholar
  143. Reed NA, Cai D, Blasius TL et al (2006) Microtubule acetylation promotes kinesin-1 binding and transport. Curr Biol 16:2166–2172PubMedCrossRefGoogle Scholar
  144. Reim K, Mansour M, Varoqueaux F et al (2001) Complexins regulate a late step in Ca2+-dependent neurotransmitter release Cell 104:71–81PubMedCrossRefGoogle Scholar
  145. Reisine TD, Fields JZ, Stern LZ et al (1977) Alterations in dopaminergic receptors in Huntington’s disease. Life Sci 21:1123–1128PubMedCrossRefGoogle Scholar
  146. Reynolds GP, Pearson SJ (1987) Decreased glutamic acid and increased 5-hydroxytryptamine in Huntington’s disease brain. Neurosci Lett 78:233–238PubMedCrossRefGoogle Scholar
  147. Ribchester RR, Thomson D, Wood NI et al (2004) Progressive abnormalities in skeletal muscle and neuromuscular junctions of transgenic mice expressing the Huntington’s disease mutation. Eur J Neurosci 20:3092–3114PubMedCrossRefGoogle Scholar
  148. Richfield EK, Herkenham M (1994) Selective vulnerability in Huntington’s disease: preferential loss of cannabinoid receptors in lateral globus pallidus. Ann Neurol 36:577–584PubMedCrossRefGoogle Scholar
  149. Rizo J, Südhof TC (2002) SNAREs and munc-18 in synaptic vesicle fusion. Nat Rev Neurosci 3:641–653PubMedGoogle Scholar
  150. Rong J, McGuire JR, Fang ZH et al (2006) Regulation of intracellular trafficking of huntingtin-associated protein-1 is critical for TrkA protein levels and neurite outgrowth. J Neurosci 26:6019–6030PubMedCrossRefGoogle Scholar
  151. Rosenmund C, Rettig J, Brose N (2003) Molecular mechanisms of active zone function. Curr Opin Neurobiol 13:509–519PubMedCrossRefGoogle Scholar
  152. Ross CA, Wood JD, Schilling G et al (1999) Polyglutamine pathogenesis. Philos Trans R Soc Lond B Biol Sci 354:1005–1011PubMedCrossRefGoogle Scholar
  153. Sapp E, Penney J, Young A et al (1999) Axonal transport of N-terminal huntingtin suggests early pathology of corticostriatal projections in Huntington disease. J Neuropathol Exp Neurol 58:165–173PubMedCrossRefGoogle Scholar
  154. Sawada K, Young CE, Barr AM et al (2002) Altered immunoreactivity of complexin protein in prefrontal cortex in severe mental illness. Mol Psychiatry 7:484–492PubMedCrossRefGoogle Scholar
  155. Sawada K, Barr AM, Nakamura M et al (2005) Hippocampal complexin proteins and cognitive dysfunction in schizophrenia. Arch Gen Psychiatry 62:263–272PubMedCrossRefGoogle Scholar
  156. Schaub JR, Lu X, Doneske B et al (2006) Hemifusion arrest by complexin is relieved by Ca2+-synaptotagmin I. Nat Struct Mol Biol 13:748–750PubMedCrossRefGoogle Scholar
  157. Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791PubMedCrossRefGoogle Scholar
  158. Shehadeh J, Fernandes HB, Zeron Mullins MM et al (2006) Striatal neuronal apoptosis is preferentially enhanced by NMDA receptor activation in YAC transgenic mouse model of Huntington disease. Neurobiol Dis 21:392–403PubMedCrossRefGoogle Scholar
  159. Shoulson I, Fahn S (1979) Huntington’s disease: clinical care and evaluation. Neurology 29:1–3PubMedCrossRefGoogle Scholar
  160. Sinadinos C, Burbidge-King T, Soh D et al (2009) Live axonal transport disruption by mutant huntingtin fragments in Drosophila motor neuron axons. Neurobiol Dis 34:389–395PubMedCrossRefGoogle Scholar
  161. Singaraja RR, Hadano S, Metzler M et al (2002) HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis. Hum Mol Genet 11:2815–2828PubMedCrossRefGoogle Scholar
  162. Sittler A, Walter S, Wedemeyer N et al (1998) SH3GL3 associates with the Huntingtin exon 1 protein and promotes the formation of polygln-containing protein aggregates. Mol Cell 2:427–436PubMedCrossRefGoogle Scholar
  163. Smith R, Brundin P, Li JY (2005) Synaptic dysfunction in Huntington’s disease: a new perspective. Cell Mol Life Sci 62:1901–1912PubMedCrossRefGoogle Scholar
  164. Smith R, Chung H, Rundquist S et al (2006) Cholinergic neuronal defect without cell loss in Huntington’s disease. Hum Mol Genet 15:3119–3131PubMedCrossRefGoogle Scholar
  165. Smith R, Klein P, Koc-Schmitz Y et al (2007) Loss of SNAP-25 and rabphilin 3a in sensory-motor cortex in Huntington’s disease. J Neurochem 103:115–123PubMedGoogle Scholar
  166. Snell RG, MacMillan JC, Cheadle JP et al (1993) Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington’s disease. Nat Genet 4:393–397PubMedCrossRefGoogle Scholar
  167. Sollner T, Bennett MK, Whiteheart SW et al (1993) A protein assembly-dissambly pathway in vitro that may correspond to sequential steps of synaptic vesicle docking, activation and fusion. Cell 75:2213–2217CrossRefGoogle Scholar
  168. Spires TL, Grote HE, Garry S et al (2004) Dendritic spine pathology and deficits in experience-dependent dendritic plasticity in R6/1 Huntington’s disease transgenic mice. Eur J Neurosci 19:2799–2807PubMedCrossRefGoogle Scholar
  169. Spokes EG (1980) Neurochemical alterations in Huntington’s chorea: a study of post-mortem brain tissue. Brain 103:179–210PubMedCrossRefGoogle Scholar
  170. Stack EC, Kubilus JK, Smith KM et al (2005) Chronology of behavioral symptoms and neuropathological sequela in R6/2 Huntington’s disease transgenic mice. J Comp Neurol 490:354–370PubMedCrossRefGoogle Scholar
  171. Starling AJ, Andre VM, Cepeda C et al (2005) Alterations in N-methyl-D-aspartate receptor sensitivity and magnesium blockade occur early in development in the R6/2 mouse model of Huntington’s disease. J Neurosci Res 82:377–386PubMedCrossRefGoogle Scholar
  172. Steward LJ, Bufton KE, Hopkins PC et al (1993) Reduced levels of 5-HT3 receptor recognition sites in the putamen of patients with Huntington’s disease. Eur J Pharmacol 242:137–143PubMedCrossRefGoogle Scholar
  173. Strauss ME, Brandt J (1990) Are there neuropsychologic manifestations of the gene for Huntington’s disease in asymptomatic, at-risk individuals? Arch Neurol 47:905–908PubMedCrossRefGoogle Scholar
  174. Südhof T (1995) The synaptic vesicle cycle: a cascade of protein-protein interactions. Nature 375:645–653PubMedCrossRefGoogle Scholar
  175. Südhof TC (2004) The synaptic vesicle cycle. Annu Rev Neurosci 27:509–547PubMedCrossRefGoogle Scholar
  176. Szebenyi G, Morfini GA, Babcock A et al (2003) Neuropathogenic forms of huntingtin and androgen receptor inhibit fast axonal transport. Neuron 40:41–52PubMedCrossRefGoogle Scholar
  177. Tang TS, Tu H, Chan EY et al (2003) Huntingtin and huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1. Neuron 39:227–239PubMedCrossRefGoogle Scholar
  178. Tannenberg RK, Scott HL, Tannenberg AE et al (2006) Selective loss of synaptic proteins in Alzheimer’s disease: Evidence for an increased severity with APOE varepsilon4. Neurochem Int 49:631–639PubMedCrossRefGoogle Scholar
  179. Tippett LJ, Waldvogel HJ, Thomas SJ et al (2007) Striosomes and mood dysfunction in Huntington’s disease. Brain 130:206–221PubMedCrossRefGoogle Scholar
  180. Tokumaru H, Umayahara K, Pellegrini LL et al (2001) SNARE Complex oligomerization by synaphin/complexin is essential for synaptic vesicle exocytosis. Cell 104:421–432PubMedCrossRefGoogle Scholar
  181. Trushina E, Dyer RB, Badger JD, 2nd et al (2004) Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. Mol Cell Biol 24:8195–8209PubMedCrossRefGoogle Scholar
  182. Usdin MT, Shelbourne PF, Myers RM et al (1999) Impaired synaptic plasticity in mice carrying the Huntington’s disease mutation. Hum Mol Genet 8:839–846PubMedCrossRefGoogle Scholar
  183. van Oostrom JC, Maguire RP, Verschuuren-Bemelmans CC et al (2005) Striatal dopamine D2 receptors, metabolism, and volume in preclinical Huntington disease. Neurology 65:941–943PubMedCrossRefGoogle Scholar
  184. Velier J, Kim MT, Schwarz C et al (1998) Wild-type and mutant huntingtins function in vesicle trafficking in the secretory and endocytic pathways. Exp Neurol 152:34–40PubMedCrossRefGoogle Scholar
  185. Vetter JM, Jehle T, Heinemeyer J et al (2003) Mice transgenic for exon 1 of Huntington’s disease: properties of cholinergic and dopaminergic pre-synaptic function in the striatum. J Neurochem 85:1054–1063PubMedCrossRefGoogle Scholar
  186. Vonsattel JP, Myers RH, Stevens TJ et al (1985) Neuropathological classification of Huntington’s disease. J Neuropathol Exp Neurol 44:559–577PubMedCrossRefGoogle Scholar
  187. Vonsattel JPG, DiFiglia M (1998) Huntington disease. J Neuropathol Exp Neurol 57:369–384PubMedCrossRefGoogle Scholar
  188. Wade A, Jacobs P, Morton AJ (2008) Atrophy and degeneration in sciatic nerve of presymptomatic mice carrying the Huntington’s disease mutation. Brain Res 1188:61–68PubMedCrossRefGoogle Scholar
  189. Waeber C, Palacios JM (1989) Serotonin-1 receptor binding sites in the human basal ganglia are decreased in Huntington’s chorea but not in Parkinson’s disease: a quantitative in vitro autoradiography study. Neuroscience 32:337–347PubMedCrossRefGoogle Scholar
  190. Waeber C, Rigo M, Chinaglia G et al (1991) Beta-adrenergic receptor subtypes in the basal ganglia of patients with Huntington’s chorea and Parkinson’s disease. Synapse 8:270–280PubMedCrossRefGoogle Scholar
  191. Walsh DM, Klyubin I, Fadeeva JV et al (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–539PubMedCrossRefGoogle Scholar
  192. Wanderer J, Morton AJ (2007) Differential morphology and composition of inclusions in the R6/2 mouse and PC12 cell models of Huntington’s disease. Histochem Cell Biol 127:473–484PubMedCrossRefGoogle Scholar
  193. Wang CE, Zhou H, McGuire JR et al (2008) Suppression of neuropil aggregates and neurological symptoms by an intracellular antibody implicates the cytoplasmic toxicity of mutant huntingtin. J Cell Biol 181:803–816PubMedCrossRefGoogle Scholar
  194. Wanker EE, Rovira C, Scherzinger E et al (1997) HIP-I: a huntingtin interacting protein isolated by the yeast two-hybrid system. Hum Mol Genet 6:487–495PubMedCrossRefGoogle Scholar
  195. Waterman-Storer CM, Karki SB, Kuznetsov SA et al (1997) The interaction between cytoplasmic dynein and dynactin is required for fast axonal transport. Proc Natl Acad Sci U S A 94:12180–12185PubMedCrossRefGoogle Scholar
  196. Weeks RA, Cunningham VJ, Piccini P et al (1997) 11C-diprenorphine binding in Huntington’s disease: a comparison of region of interest analysis with statistical parametric mapping. J Cereb Blood Flow Metab 17:943–949PubMedCrossRefGoogle Scholar
  197. Witzmann FA, Li J, Strother WN et al (2003) Innate differences in protein expression in the nucleus accumbens and hippocampus of inbred alcohol-preferring and -nonpreferring rats. Proteomics 3:1335–1344PubMedCrossRefGoogle Scholar
  198. Wong EH, Reynolds GP, Bonhaus DW et al (1996) Characterization of [3H]GR 113808 binding to 5-HT4 receptors in brain tissues from patients with neurodegenerative disorders. Behav Brain Res 73:249–252PubMedCrossRefGoogle Scholar
  199. Wyttenbach A, Carmichael J, Swartz J et al (2000) Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington’s disease. Proc Natl Acad Sci U S A 97:2898–2903PubMedCrossRefGoogle Scholar
  200. Xue M, Reim K, Chen X et al (2007) Distinct domains of complexin I differentially regulate neurotransmitter release. Nat Struct Mol Biol 14:949–958PubMedCrossRefGoogle Scholar
  201. Yi JH, Hoover R, McIntosh TK et al (2006) Early, transient increase in complexin I and complexin II in the cerebral cortex following traumatic brain injury is attenuated by N-acetylcysteine. J Neurotrauma 23:86–96PubMedCrossRefGoogle Scholar
  202. Young AB, Shoulson I, Penney JB (1986) Huntington’s disease in Venezuela: neurologic feature and functional decline. Neurology 36:244–249PubMedCrossRefGoogle Scholar
  203. Young AB, Greenamyre JT, Hollingsworth Z et al (1988) NMDA receptor losses in putamen from patients with Huntington’s disease. Science 241:981–983PubMedCrossRefGoogle Scholar
  204. Zabel C, Sagi D, Kaindl AM et al (2006) Comparative proteomics in neurodegenerative and non-neurodegenerative diseases suggest nodal point proteins in regulatory networking. J Proteome Res 5:1948–1958PubMedCrossRefGoogle Scholar
  205. Zechner U, Scheel S, Hemberger M et al (1998) Characterization of the mouse Src homology 3 domain gene Sh3d2c on Chr 7 demonstrates coexpression with huntingtin in the brain and identifies the processed pseudogene Sh3d2c-ps1 on Chr 2. Genomics 54:505–510PubMedCrossRefGoogle Scholar
  206. Zeron MM, Chen N, Moshaver A et al (2001) Mutant huntingtin enhances excitotoxic cell death. Mol Cell Neurosci 17:41–53PubMedCrossRefGoogle Scholar
  207. Zeron MM, Hansson O, Chen N (2002) Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington’s disease. Neuron 33:849–860PubMedCrossRefGoogle Scholar
  208. Zeron MM, Fernandes HB, Krebs C et al (2004) Potentiation of NMDA receptor-mediated excitotoxicity linked with intrinsic apoptotic pathway in YAC transgenic mouse model of Huntington’s disease. Mol Cell Neurosci 25:469–479PubMedCrossRefGoogle Scholar
  209. Zink M, Vollmayr B, Gebicke-Haerter PJ et al (2007) Reduced expression of complexins I and II in rats bred for learned helplessness. Brain Res 1144:202–208PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of PharmacologyUniversity of CambridgeCambridgeUK

Personalised recommendations