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.
|Original language||English (US)|
|State||Published - May 30 2017|
Bibliographical noteKAUST Repository Item: Exported on 2020-10-01
Acknowledged KAUST grant number(s): OSR-2015-CRG4-2602
Acknowledgements: This work was supported in part by Inserm, the Université Pierre et Marie Curie (UPMC, Paris 6), and an ERC advanced investigator grant (#250349) to J.-A.G. A.G. was partly supported by the King Abdullah University of Science and Technology (KAUST) Office of Sponsored Research award (#OSR-2015-CRG4-2602) to J.-A.G. and Stefan Arold. J.-C.P. lab is supported by grants from the Human Frontier Science Program (RGP0022/2013) and the Fondation pour la Recherche Médicale (DEQ20140329539). Q.C. and C.S. were recipients of doctoral fellowships of UPMC. Equipment at the IFM was also supported by DIM NeRF from Région Ile-de-France and by the FRC/Rotary ‘Espoir en tête’. Microscopy was carried out at the Institut du Fer à Moulin Cell and Tissue Imaging facility. Labs of J.-A.G. and J.-C.P. are affiliated with the Paris School of Neuroscience (ENP) and the Bio-Psy Laboratory of excellence. Work in S.G. and J.A. labs was supported by Ministerio de Ciencia e Innovación (SAF2015-67474-R; MINECO/FEDER to S.G. and SAF2014-57160 to J.A.), Fundacio La Marato TV3, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, R006/0010/0006). We thank Ana López and Maria Teresa Muñoz for technical assistance, and Teresa Rodrigo Calduch and the staff of the animal care facility (Facultat de Psicologia, Universitat de Barcelona) for their help.
This publication acknowledges KAUST support, but has no KAUST affiliated authors.