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Nat Commun. 2017 May 30;8:15592. doi: 10.1038/ncomms15592.

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

Giralt A1,2,3, Brito V4,5,6,7, Chevy Q1,2,3, Simonnet C1,2,3, Otsu Y1,2,3, Cifuentes-Díaz C1,2,3, de Pins B1,2,3, Coura R1,2,3, Alberch J4,5,6,7, Ginés S4,5,6,7, Poncer JC1,2,3, Girault JA1,2,3.

Author information

1
Inserm UMR-S 839, 75005 Paris, France.
2
Université Pierre &Marie Curie, Sorbonne Universités, 75005 Paris, France.
3
Institut du Fer a Moulin, 75005 Paris, France.
4
Departament de Biomedicina, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain.
5
Institut d'Investigacions Biomèdiques August Pii Sunyer (IDIBAPS), 08036 Barcelona, Spain.
6
Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain.
7
Institut de Neurociencies, Universitat de Barcelona, 08036 Barcelona, Spain.

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.

PMID:
28555636
PMCID:
PMC5459995
DOI:
10.1038/ncomms15592
[Indexed for MEDLINE]
Free PMC Article

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