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Cited by 114Genetic Neurodegenerative DiseasesNeuroscience and Neuropharmacology ResearchGenetics and Neurodevelopmental Disorders

Neurotrophin receptor p75NTR mediates Huntington’s disease–associated synaptic and memory dysfunction

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Brito, Verónica, Giralt, Albert, Enriquez-Barreto, Lilian, Puigdellívol, Mar, Suelves, Nuria, Zamora-Moratalla, Alfonsa, Ballesteros, Jesús J., Martín, Eduardo D. +4 more·2014·Journal of Clinical Investigation
DOI 10.1172/jci74809PMC PMC4191006
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Abstract

Learning and memory deficits are early clinical manifestations of Huntington's disease (HD). These cognitive impairments have been mainly associated with frontostriatal HD pathology; however, compelling evidence provided by several HD murine models suggests that the hippocampus may contribute to synaptic deficits and memory dysfunction in HD. The neurotrophin receptor p75(NTR) negatively regulates spine density, which is associated with learning and memory; therefore, we explored whether disturbed p75(NTR) function in the hippocampus could contribute to synaptic dysfunction and memory deficits in HD. Here, we determined that levels of p75(NTR) are markedly increased in the hippocampus of 2 distinct mouse models of HD and in HD patients. Normalization of p75(NTR) levels in HD mutant mice heterozygous for p75(NTR) prevented memory and synaptic plasticity deficits and ameliorated dendritic spine abnormalities, likely through normalization of the activity of the GTPase RhoA. Moreover, viral-mediated overexpression of p75(NTR) in the hippocampus of WT mice reproduced HD learning and memory deficits, while knockdown of p75(NTR) in the hippocampus of HD mice prevented cognitive decline. Together, these findings provide evidence of hippocampus-associated memory deficits in HD and demonstrate that p75(NTR) mediates synaptic, learning, and memory dysfunction in HD.

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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 [203]

  • Increased p75NTR levels are accompanied by long-term memory deficits, altered LTP, reduced levels of synaptic proteins, decreased dendritic spine density, and increased activation of RhoA.

    “Increased p75NTR levels were accompanied by long-term memory deficits, altered LTP, reduced levels of synaptic proteins, decreased dendritic spine density, and increased activation of RhoA [203].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [203]

  • Direct inhibition of RhoA using C3 transferase ameliorates dendritic spine abnormalities in primary hippocampal cultures.

    “Likewise, direct inhibition of RhoA using C3 transferase ameliorated dendritic spine abnormalities in primary hippocampal cultures [203].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [203]

  • 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 [203]

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Authors
Brito, V., Giralt, A., Enriquez-Barreto, L., Puigdellívol, M., Suelves, N., Zamora-Moratalla, A., Ballesteros, J. J., Martín, E. D., Dominguez-Iturza, N., Morales, M., Alberch, J., & Ginés, S.
Affiliations
  • Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
  • University of Castilla-La Mancha (ES)
  • Center for Biomedical Research of La Rioja (ES)
Corresponding author
Ginés, Sílvia
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2014-09-02
Volume
124
Issue
10
Pages
4411-4428
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci74809
PMC
PMC4191006
OpenAlex
W1979333165
Cited by
114
References
4
Citations by year
2026: 3 · 2025: 8 · 2024: 4 · 2023: 7 · 2022: 13 · 2021: 18 · 2020: 10 · 2019: 12 · 2018: 16 · 2017: 10 · 2016: 7 · 2015: 6
FWCI
3.22
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (publishedVersion)
  • RECERCAT (Consorci de Serveis Universitaris de Catalunya) (submittedVersion, public-domain)
Funders
  • Ministerio de Economía y Competitividad (SAF2012-39142, SAF2011-29507, RD06/0010/0006, SAF2012)
  • KU Leuven
  • Universitat de Barcelona
  • Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CB06/05/0042, CB06/05/0054)
  • Instituto de Salud Carlos III (RD06/0010/0006)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
Huntington's disease, p75 neurotrophin receptor, hippocampus, synaptic dysfunction, memory impairment, dendritic spines, RhoA GTPase, synaptic plasticity, learning deficits, viral overexpression, knockdown
MeSH terms
Animals, Astrocytes, Cells, Cultured, Electrophysiology, Heterozygote, Hippocampus, Humans, Huntington Disease, Learning, Male, Memory, Memory Disorders, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Synapses, Receptors, Nerve Growth Factor, Microscopy, Confocal, Mice, Gene Knock-In Techniques

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