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Cited by 187Genetic Neurodegenerative DiseasesNerve injury and regenerationNeuroscience and Neuropharmacology Research

Impaired TrkB receptor signaling underlies corticostriatal dysfunction in Huntington’s disease

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Plotkin, Joshua L., Day, Michelle, Peterson, Jayms D., Xie, Zhong, Kress, Geraldine J., Rafalovich, Igor, Kondapalli, Jyothisri, Gertler, Tracy S. +7 more·2014·Neuron
DOI 10.1016/j.neuron.2014.05.032PMC PMC4131293
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Abstract

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. The debilitating choreic movements that plague HD patients have been attributed to striatal degeneration induced by the loss of cortically supplied brain-derived neurotrophic factor (BDNF). Here, we show that in mouse models of early symptomatic HD, BDNF delivery to the striatum and its activation of tyrosine-related kinase B (TrkB) receptors were normal. However, in striatal neurons responsible for movement suppression, TrkB receptors failed to properly engage postsynaptic signaling mechanisms controlling the induction of potentiation at corticostriatal synapses. Plasticity was rescued by inhibiting p75 neurotrophin receptor (p75NTR) signaling or its downstream target phosphatase-and-tensin-homolog-deleted-on-chromosome-10 (PTEN). Thus, corticostriatal synaptic dysfunction early in HD is attributable to a correctable defect in the response to BDNF, not its delivery.

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  • p75NTR is increased in HD mouse models and in postmortem samples from HD patients.

    “p75NTR was increased in HD mouse models and in postmortem samples from HD patients [203,204].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [204]

    The Results section reports that p75NTR mRNA expression was not measurably different in the HD mouse neurons studied; the Discussion attributes increased p75NTR signaling to elevated PTEN, not increased p75NTR itself. The cited passages do not report p75NTR expression in postmortem samples from HD patients. (LLM, conf=0.88)

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  • Normalizing p75NTR signaling prevents memory and synaptic deficits in HD mutant mice.

    “Normalizing p75NTR signaling prevented memory and synaptic deficits in HD mutant mice [203,204,205,208].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [204]

    The Results section (page not available in our copy) reports that reducing p75NTR expression restored BDNF-dependent synaptic potentiation in neurons from BACHD mice. It does not report that this intervention prevented memory deficits, or that it prevented synaptic deficits from developing in the mice. (LLM, conf=0.88)

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Research works printed but not linked: 59

  1. Altar CA Cai N Bliven T Juhasz M Conner JM Acheson AL Lindsay RM Wiegand SJ Anterograde transport of brain-derived neurotrophic factor and its role in the brain Nature 1997 389 856 860 9349818
  2. Anders S Huber W Differential expression analysis for sequence count data Genome Biol 2010 11 R106 20979621 PMC3218662
  3. André VM Cepeda C Fisher YE Huynh M Bardakjian N Singh S Yang XW Levine MS Differential electrophysiological changes in striatal output neurons in Huntington's disease Journal of Neuroscience 2011 31 1170 1182 21273402 PMC3071260
  4. Arenkiel BR Peca J Davison IG Feliciano C Deisseroth K Augustine GJ Ehlers MD Feng G In vivo light-induced activation of neural circuitry in transgenic mice expressing channelrhodopsin-2 Neuron 2007 54 205 218 17442243 PMC3634585
  5. Besusso D Geibel M Kramer D Schneider T Pendolino V Picconi B Calabresi P Bannerman DM Minichiello L BDNF-TrkB signaling in striatopallidal neurons controls inhibition of locomotor behavior Nat Commun 2013 4 2031 23774276 PMC3940866
  6. Bothwell M Functional interactions of neurotrophins and neurotrophin receptors Annu Rev Neurosci 1995 18 223 253 7605062
  7. Brito V Puigdellívol M Giralt A del Toro D Alberch J Ginés S Imbalance of p75(NTR)/TrkB protein expression in Huntington's disease: implication for neuroprotective therapies Cell Death Dis 2013 4 e595 23598407 PMC3641339
  8. Calabresi P Picconi B Tozzi A Di Filippo M Dopamine-mediated regulation of corticostriatal synaptic plasticity Trends Neurosci 2007 30 211 219 17367873
  9. Canals JM Pineda JR Torres-Peraza JF Bosch M Martín-Ibañez R Muñoz MT Mengod G Ernfors P Alberch J Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington's disease Journal of Neuroscience 2004 24 7727 7739 15342740 PMC6729627
  10. Cepeda C Wu N André VM Cummings DM Levine MS The corticostriatal pathway in Huntington's disease Prog Neurobiol 2007 81 253 271 17169479 PMC1913635
  11. Chan CS Peterson JD Gertler TS Glajch KE Quintana RE Cui Q Sebel LE Plotkin JL Shen W Heiman M Strain-Specific Regulation of Striatal Phenotype in Drd2-eGFP BAC Transgenic Mice Journal of Neuroscience 2012 32 9124 9132 22764222 PMC3461272
  12. Day M Wokosin D Plotkin JL Tian X Surmeier DJ Differential excitability and modulation of striatal medium spiny neuron dendrites Journal of Neuroscience 2008 28 11603 11614 18987196 PMC3235729
  13. Dechant G Barde Y-A The neurotrophin receptor p75(NTR): novel functions and implications for diseases of the nervous system Nat Neurosci 2002 5 1131 1136 12404007
  14. Ding J Peterson JD Surmeier DJ Corticostriatal and thalamostriatal synapses have distinctive properties Journal of Neuroscience 2008 28 6483 6492 18562619 PMC3461269
  15. Eswarakumar VP Lax I Schlessinger J Cellular signaling by fibroblast growth factor receptors Cytokine Growth Factor Rev 2005 16 139 149 15863030
  16. Fayard B Loeffler S Weis J Vögelin E Krüttgen A The secreted brain-derived neurotrophic factor precursor pro-BDNF binds to TrkB and p75NTR but not to TrkA or TrkC J Neurosci Res 2005 80 18 28 15704182
  17. Flajolet M Wang Z Futter M Shen W Nuangchamnong N Bendor J Wallach I Nairn AC Surmeier DJ Greengard P FGF acts as a co-transmitter through adenosine A(2A) receptor to regulate synaptic plasticity Nat Neurosci 2008 11 1402 1409 18953346 PMC2779562
  18. Gauthier LR Charrin BC Borrell-Pagès M Dompierre JP Rangone H Cordelières FP De Mey J MacDonald ME Lessmann V Humbert S Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules Cell 2004 118 127 138 15242649
  19. Gerfen CR Surmeier DJ Modulation of Striatal Projection Systems by Dopamine Annu Rev Neurosci 2011 34 441 466 21469956 PMC3487690
  20. Gericke A Munson M Ross AH Regulation of the PTEN phosphatase Gene 2006 374 1 9 16675164
  21. Ginés S Paoletti P Alberch J Impaired TrkB-mediated ERK1/2 activation in huntington disease knock-in striatal cells involves reduced p52/p46 Shc expression J Biol Chem 2010 285 21537 21548 20442398 PMC2898383
  22. Gray M Shirasaki DI Cepeda C André VM Wilburn B Lu X-H Tao J Yamazaki I Li S-H Sun YE Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice Journal of Neuroscience 2008 28 6182 6195 18550760 PMC2630800
  23. Harrison LM Muller SH Spano D Effects of the Ras homolog Rhes on Akt/protein kinase B and glycogen synthase kinase 3 phosphorylation in striatum Neuroscience 2013 236 21 30 23380502 PMC3596425
  24. Harrison LM Lahoste GJ The role of Rhes, Ras homolog enriched in striatum, in neurodegenerative processes Exp. Cell Res 2013 319 2310 2315 23583659
  25. Hu J Ge H Newman M Liu K OSA: a fast and accurate alignment tool for RNA-Seq Bioinformatics 2012 28 1933 1934 22592379
  26. Huber LJ Chao MV Mesenchymal and neuronal cell expression of the p75 neurotrophin receptor gene occur by different mechanisms Dev. Biol 1995 167 227 238 7851645
  27. Humbert S Bryson EA Cordelières FP Connors NC Datta SR Finkbeiner S Greenberg ME Saudou F The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt Dev. Cell 2002 2 831 837 12062094
  28. Ilag LL Rottenberger C Liepinsh E Wellnhofer G Rudert F Otting G Ilag LL Selection of a peptide ligand to the p75 neurotrophin receptor death domain and determination of its binding sites by NMR Biochem Biophys Res Commun 1999 255 104 109 10082663
  29. Jia Y Gall CM Lynch G Presynaptic BDNF promotes postsynaptic long-term potentiation in the dorsal striatum J Neurosci 2010 30 14440 14445 20980601 PMC2972744
  30. Kasai H Fukuda M Watanabe S Hayashi-Takagi A Noguchi J Structural dynamics of dendritic spines in memory and cognition Trends Neurosci 2010 33 121 129 20138375
  31. Heikkinen T Lehtimäki K Vartiainen N Puoliväli J Hendricks SJ Glaser JR Bradaia A Wadel K Touller C Kontkanen O Characterization of neurophysiological and behavioral changes, MRI brain volumetry and 1H MRS in zQ175 knock-in mouse model of Huntington's disease PLoS ONE 2012 7 e50717 23284644 PMC3527436
  32. Kopec CD Li B Wei W Boehm J Malinow R Glutamate receptor exocytosis and spine enlargement during chemically induced long-term potentiation Journal of Neuroscience 2006 26 2000 2009 16481433 PMC6674938
  33. Kreitzer AC Malenka RC Striatal plasticity and basal ganglia circuit function Neuron 2008 60 543 554 19038213 PMC2724179
  34. Kung VWS Hassam R Morton AJ Jones S Dopamine-dependent long term potentiation in the dorsal striatum is reduced in the R6/2 mouse model of Huntington's disease Neuroscience 2007 146 1571 1580 17478055
  35. Menalled LB Chesselet M-F Mouse models of Huntington's disease Trends Pharmacol Sci 2002 23 32 39 11804649
  36. Menalled LB Kudwa AE Miller S Fitzpatrick J Watson-Johnson J Keating N Ruiz M Mushlin R Alosio W McConnell K Comprehensive behavioral and molecular characterization of a new knock-in mouse model of Huntington's disease: zQ175 PLoS ONE 2012 7 e49838 23284626 PMC3527464
  37. Mendez P De Roo M Poglia L Klauser P Muller D N-cadherin mediates plasticity-induced long-term spine stabilization J. Cell Biol 2010 189 589 600 20440002 PMC2867305
  38. Milnerwood AJ Gladding CM Pouladi MA Kaufman AM Hines RM Boyd JD Ko RWY Vasuta OC Graham RK Hayden MR Early increase in extrasynaptic NMDA receptor signaling and expression contributes to phenotype onset in Huntington's disease mice Neuron 2010 65 178 190 20152125
  39. Minichiello L Calella AM Medina DL Bonhoeffer T Klein R Korte M Mechanism of TrkB-mediated hippocampal long-term potentiation Neuron 2002 36 121 137 12367511
  40. Morgenstern PF Marongiu R Musatov SA Kaplitt MG Adeno-associated viral gene delivery in neurodegenerative disease Methods Mol. Biol 2011 793 443 455 21913118
  41. Okamoto S-I Pouladi MA Talantova M Yao D Xia P Ehrnhoefer DE Zaidi R Clemente A Kaul M Graham RK Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin Nat Med 2009 15 1407 1413 19915593 PMC2789858
  42. Petreanu L Mao T Sternson SM Svoboda K The subcellular organization of neocortical excitatory connections Nature 2009 457 1142 1145 19151697 PMC2745650
  43. Pfister C Tatabiga MS Roser F Selection of suitable reference genes for quantitative real-time polymerase chain reaction in human meningiomas and arachnoidea BMC Res Notes 2011 4 275 21806841 PMC3166272
  44. Plotkin JL Day M Surmeier DJ Synaptically driven state transitions in distal dendrites of striatal spiny neurons Nat Neurosci 2011 PMC3235762 21666674
  45. Raymond LA Andre VM Cepeda C Gladding CM Milnerwood AJ Levine MS Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function Neuroscience 2011 198 252 273 21907762 PMC3221774
  46. Shen W Flajolet M Greengard P Surmeier DJ Dichotomous Dopaminergic Control of Striatal Synaptic Plasticity Science 2008 321 848 851 18687967 PMC2833421
  47. Song W Volosin M Cragnolini AB Hempstead BL Friedman WJ ProNGF induces PTEN via p75NTR to suppress Trk-mediated survival signaling in brain neurons Journal of Neuroscience 2010 30 15608 15615 21084616 PMC2996105
  48. Subramaniam S Sixt KM Barrow R Snyder SH Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity Science 2009 324 1327 1330 19498170 PMC2745286
  49. Tooyama I Kremer HP Hayden MR Kimura H McGeer EG McGeer PL Acidic and basic fibroblast growth factor-like immunoreactivity in the striatum and midbrain in Huntington's disease Brain Res 1993 610 1 7 7686078
  50. Warby SC Chan EY Metzler M Gan L Singaraja RR Crocker SF Robertson HA Hayden MR Huntingtin phosphorylation on serine 421 is significantly reduced in the striatum and by polyglutamine expansion in vivo Hum Mol Genet 2005 14 1569 1577 15843398
  51. Wexler NS Young AB Tanzi RE Travers H Starosta-Rubinstein S Penney JB Snodgrass SR Shoulson I Gomez F Ramos Arroyo MA Homozygotes for Huntington's disease Nature 1987 326 194 197 2881213
  52. Xu-Friedman MA Regehr WG Probing fundamental aspects of synaptic transmission with strontium J Neurosci 2000 20 4414 4422 10844010 PMC6772435
  53. Yamashita T Tohyama M The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI Nat Neurosci 2003 6 461 467 12692556
  54. Yang S Kim H-M The RhoA-ROCK-PTEN pathway as a molecular switch for anchorage dependent cell behavior Biomaterials 2012 33 2902 2915 22244698
  55. Zhang Y Li M Drozda M Chen M Ren S Mejia Sanchez RO Leavitt BR Cattaneo E Ferrante RJ Hayden MR Depletion of wild-type huntingtin in mouse models of neurologic diseases J Neurochem 2003 87 101 106 12969257
  56. Zhang YH Chi XX Nicol GD Brain-derived neurotrophic factor enhances the excitability of rat sensory neurons through activation of the p75 neurotrophin receptor and the sphingomyelin pathway J Physiol (Lond) 2008 586 3113 3127 18450779 PMC2538774
  57. Zuccato C Ciammola A Rigamonti D Leavitt BR Goffredo D Conti L MacDonald ME Friedlander RM Silani V Hayden MR Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease Science 2001 293 493 498 11408619
  58. Zuccato C Cattaneo E Role of brain-derived neurotrophic factor in Huntington's disease Prog Neurobiol 2007 81 294 330 17379385
  59. Zuccato C Valenza M Cattaneo E Molecular mechanisms and potential therapeutical targets in Huntington's disease Physiol Rev 2010 90 905 981 20664076

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Authors
Plotkin, J. L., Day, M., Peterson, J. D., Xie, Z., Kress, G. J., Rafalovich, I., Kondapalli, J., Gertler, T. S., Flajolet, M., Greengard, P., Stavarache, M., Kaplitt, M. G., Rosinski, J., Chan, C. S., & Surmeier, D. J.
Affiliations
  • Northwestern University (US)
  • Rockefeller University (US)
  • Weill Cornell Medicine (US)
  • CHDI Foundation (US)
Corresponding author
Surmeier, D. James
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2014-07
Volume
83
Issue
1
Pages
178-188
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2014.05.032
PMC
PMC4131293
OpenAlex
W1995051993
Cited by
187
References
5
Citations by year
2026: 5 · 2025: 5 · 2024: 12 · 2023: 20 · 2022: 18 · 2021: 15 · 2020: 15 · 2019: 14 · 2018: 22 · 2017: 19 · 2016: 23 · 2015: 16 · 2014: 3
FWCI
8.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Mental Health (MH-074866, P50MH074866)
  • National Institute of Neurological Disorders and Stroke (NS067414, R01NS067414, R01NS034696, NS034696, R37NS034696)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
Huntington's disease, brain-derived neurotrophic factor, corticostriatal synapses, striatal neurons, synaptic plasticity, p75 neurotrophin receptor, PTEN, chorea, striatal degeneration, neurotrophin signaling
MeSH terms
Animals, Cerebral Cortex, Corpus Striatum, Disease Models, Animal, Huntington Disease, Mice, Inbred C57BL, Mice, Transgenic, Organ Culture Techniques, Signal Transduction, Receptor, trkB, Mice, Gene Knock-In Techniques

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