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Cited by 102Neuroscience and Neuropharmacology ResearchGenetics and Neurodevelopmental DisordersGenetic Neurodegenerative Diseases

Pyk2 modulates hippocampal excitatory synapses and contributes to cognitive deficits in a Huntington’s disease model

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Giralt, Albert, Brito, Veronica, Chevy, Quentin, Simonnet, Clémence, Otsu, Yo, Cifuentes-Díaz, Carmen, de Pins, Benoit, Coura, Renata +4 more·2017·Nature Communications
DOI 10.1038/ncomms15592PMC PMC5459995
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Abstract

The structure and function of spines and excitatory synapses are under the dynamic control of multiple signalling networks. Although tyrosine phosphorylation is involved, its regulation and importance are not well understood. Here we study the role of Pyk2, a non-receptor calcium-dependent protein-tyrosine kinase highly expressed in the hippocampus. Hippocampal-related learning and CA1 long-term potentiation are severely impaired in Pyk2-deficient mice and are associated with alterations in NMDA receptors, PSD-95 and dendritic spines. In cultured hippocampal neurons, Pyk2 has autophosphorylation-dependent and -independent roles in determining PSD-95 enrichment and spines density. Pyk2 levels are decreased in the hippocampus of individuals with Huntington and in the R6/1 mouse model of the disease. Normalizing Pyk2 levels in the hippocampus of R6/1 mice rescues memory deficits, spines pathology and PSD-95 localization. Our results reveal a role for Pyk2 in spine structure and synaptic function, and suggest that its deficit contributes to Huntington’s disease cognitive impairments.

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Authors
Giralt, A., Brito, V., Chevy, Q., Simonnet, C., Otsu, Y., Cifuentes-Díaz, C., de Pins, B., Coura, R., Alberch, J., Ginés, S., Poncer, J.-C., & Girault, J.-A.
Affiliations
  • Inserm (FR)
  • Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
Corresponding author
Girault, Jean-Antoine
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-05-30
Volume
8
Issue
1
Pages
15592-15592
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms15592
PMC
PMC5459995
OpenAlex
W2619291451
Cited by
102
References
5
Citations by year
2026: 8 · 2025: 9 · 2024: 10 · 2023: 12 · 2022: 11 · 2021: 18 · 2020: 10 · 2019: 13 · 2018: 10 · 2017: 1
FWCI
4.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (publishedVersion, cc-by)
  • Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
  • HAL (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • RECERCAT (Consorci de Serveis Universitaris de Catalunya) (submittedVersion, cc-by)
  • King Abdullah University of Science and Technology Repository (King Abdullah University of Science and Technology) (submittedVersion)
Funders
  • Institut National de la Santé et de la Recherche Médicale
  • King Abdullah University of Science and Technology
  • Universitat de Barcelona
  • Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
  • École des Neurosciences Paris Île de France
  • FP7 Ideas: European Research Council (250349)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Keywords
Pyk2, tyrosine kinase, hippocampus, excitatory synapses, dendritic spines, PSD-95, NMDA receptor, long-term potentiation, R6/1 mouse model, Huntington's disease, cognitive impairment, memory, tyrosine phosphorylation, autophosphorylation
MeSH terms
Aged, Alleles, Animals, Behavior, Animal, Brain, Cognition Disorders, Female, Hippocampus, Humans, Huntington Disease, Male, Mice, Inbred C57BL, Microscopy, Electron, Middle Aged, Phenotype, Phosphorylation, Synapses, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Long-Term Potentiation, Mice, Knockout, Excitatory Postsynaptic Potentials, Dendritic Spines, Mice, Focal Adhesion Kinase 2

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