U. Glua1-(-#jbc1830522, . Biotechnology, A. Ny, M. Arbor, . Usa-)-#gr14161032 et al., phosphoY418-Src reacting with all phosphoSFKs mouse monoclonal antibodies All blots were incubated with the primary antibody overnight at 4 °C by shaking in PBS with 0.2 g l À 1 sodium azide. After several washes in TBS-T, blots were incubated with secondary anti-rabbit or anti-mouse IgG IRdye800CW- coupled or anti-mouse IgG IRdye700DX-coupled antibodies For loading control a mouse monoclonal antibody for a-tubulin was used, GluN2B (#2697434), GluA2 (#2280905), and GluN2A (#NRG1815904, Secondary antibody binding was detected by Odyssey infrared imaging apparatus, pp.1472-1474, 2726818.

. Data, The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary Information files or available on request from the corresponding author

J. A. Girault, A. Costa, P. Derkinderen, J. M. Studler, M. Toutant et al., CAKbeta in the nervous system: a link between neuronal activity, plasticity and survival? Trends Neurosci, pp.257-263, 1999.

M. W. Salter and L. Kalia, Src kinases: a hub for NMDA receptor regulation, Nature Reviews Neuroscience, vol.69, issue.4, pp.317-328, 2004.
DOI : 10.1074/jbc.M103501200

S. Lev, Protein tyrosine kinase PYK2 involved in Ca2+-induced regulation of ion channel and MAP kinase functions, Nature, vol.376, issue.6543, pp.737-745, 1995.
DOI : 10.1038/376737a0

A. Menegon, and PYK2/CAK??, two related tyrosine kinases highly expressed in the central nervous system: similarities and differences in the expression pattern, European Journal of Neuroscience, vol.7, issue.11, pp.3777-3788, 1999.
DOI : 10.1046/j.1460-9568.1999.00798.x

J. A. Bartos, Postsynaptic Clustering and Activation of Pyk2 by PSD-95, Journal of Neuroscience, vol.30, issue.2, pp.449-463, 2010.
DOI : 10.1523/JNEUROSCI.4992-08.2010

H. Hsin, M. J. Kim, C. F. Wang, and M. Sheng, Proline-Rich Tyrosine Kinase 2 Regulates Hippocampal Long-Term Depression, Journal of Neuroscience, vol.30, issue.36, pp.11983-11993, 2010.
DOI : 10.1523/JNEUROSCI.1029-10.2010
URL : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122232

Y. Huang, CAK?/Pyk2 Kinase Is a Signaling Link for Induction of Long-Term Potentiation in CA1 Hippocampus, Neuron, vol.29, issue.2, pp.485-496, 2001.
DOI : 10.1016/S0896-6273(01)00220-3

J. C. Lambert, Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease, Nature Genetics, vol.9, issue.12, pp.1452-1458, 2013.
DOI : 10.1093/bioinformatics/btq419

K. W. Walkiewicz, J. A. Girault, and S. T. Arold, How to awaken your nanomachines: Site-specific activation of focal adhesion kinases through ligand interactions, Progress in Biophysics and Molecular Biology, vol.119, issue.1, pp.60-71, 2015.
DOI : 10.1016/j.pbiomolbio.2015.06.001

I. Dikic, G. Tokiwa, S. Lev, S. A. Courtneidge, and J. Schlessinger, A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation, Nature, vol.383, issue.6600, pp.547-550, 1996.
DOI : 10.1038/383547a0

J. C. Siciliano, M. Toutant, P. Derkinderen, T. Sasaki, and J. A. Girault, Differential regulation of proline-rich tyrosine kinase 2/cell adhesion kinase beta (PYK2/CAKbeta) and pp125(FAK) by glutamate and depolarization in rat hippocampus, J. Biol. Chem, vol.271, pp.28942-28946, 1996.

V. Heidinger, Metabotropic glutamate receptor 1-induced upregulation of NMDA receptor current: mediation through the Pyk2/Src-family kinase pathway in cortical neurons, J. Neurosci, vol.22, pp.5452-5461, 2002.

H. Husi, M. A. Ward, J. S. Choudhary, W. P. Blackstock, and S. G. Grant, Proteomic analysis of NMDA receptor-adhesion protein signaling complexes, Nat. Neurosci, vol.3, pp.661-669, 2000.

G. K. Seabold, A. Burette, I. A. Lim, R. J. Weinberg, and J. W. Hell, Interaction of the Tyrosine Kinase Pyk2 with the N-Methyl-D-aspartate Receptor Complex via the Src Homology 3 Domains of PSD-95 and SAP102, Journal of Biological Chemistry, vol.278, issue.17, pp.15040-15048, 2003.
DOI : 10.1074/jbc.M212825200

L. Bongiorno-borbone, G. Kadare, F. Benfenati, and J. A. Girault, FAK and PYK2 interact with SAP90/PSD-95-Associated Protein-3, Biochemical and Biophysical Research Communications, vol.337, issue.2, pp.641-646, 2005.
DOI : 10.1016/j.bbrc.2005.09.099

S. G. Grant, Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice, Science, vol.258, issue.5090, pp.1903-1910, 1992.
DOI : 10.1126/science.1361685

O. Dell, T. J. Kandel, E. R. Grant, and S. G. , Long-term potentiation in the hippocampus is blocked by tyrosine kinase inhibitors, Nature, vol.353, issue.6344, pp.558-560, 1991.
DOI : 10.1038/353558a0

M. Okigaki, Pyk2 regulates multiple signaling events crucial for macrophage morphology and migration, Proc. Natl Acad. Sci. USA, pp.10740-10745, 2003.
DOI : 10.1126/science.273.5272.245
URL : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC196873

A. Giralt, R. Coura, and J. A. Girault, Pyk2 is essential for astrocytes mobility following brain lesion, Glia, vol.228, issue.4, pp.620-634, 2016.
DOI : 10.1002/glia.22952
URL : https://hal.archives-ouvertes.fr/hal-01286068

F. L. Assini, M. Duzzioni, and R. N. Takahashi, Object location memory in mice: Pharmacological validation and further evidence of hippocampal CA1 participation, Behavioural Brain Research, vol.204, issue.1, pp.206-211, 2009.
DOI : 10.1016/j.bbr.2009.06.005

J. I. Cunningham, J. Raudensky, J. Tonkiss, and B. K. Yamamoto, MDMA pretreatment leads to mild chronic unpredictable stress-induced impairments in spatial learning., Behavioral Neuroscience, vol.123, issue.5, pp.1076-1084, 2009.
DOI : 10.1037/a0016716

J. C. Corvol, Depolarization Activates ERK and Proline-rich Tyrosine Kinase 2 (PYK2) Independently in Different Cellular Compartments in Hippocampal Slices, Journal of Biological Chemistry, vol.280, issue.1, pp.660-668, 2005.
DOI : 10.1074/jbc.M411312200

N. W. Gray, R. M. Weimer, I. Bureau, and K. Svoboda, Rapid Redistribution of Synaptic PSD-95 in the Neocortex In Vivo, PLoS Biology, vol.2, issue.11, p.370, 2006.
DOI : 10.1371/journal.pbio.0040370.sd001

D. El-husseini-ael, Synaptic Strength Regulated by Palmitate Cycling on PSD-95, Cell, vol.108, issue.6, pp.849-863, 2002.
DOI : 10.1016/S0092-8674(02)00683-9

M. Colledge, Ubiquitination Regulates PSD-95 Degradation and AMPA Receptor Surface Expression, Neuron, vol.40, issue.3, pp.595-607, 2003.
DOI : 10.1016/S0896-6273(03)00687-1
URL : http://doi.org/10.1016/s0896-6273(03)00687-1

M. D. Ehlers, Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system, Nature Neuroscience, vol.6, issue.3, pp.231-242, 2003.
DOI : 10.1038/nn1013

K. Perez-de-arce, Synaptic Clustering of PSD-95 Is Regulated by c-Abl through Tyrosine Phosphorylation, Journal of Neuroscience, vol.30, issue.10, pp.3728-3738, 2010.
DOI : 10.1523/JNEUROSCI.2024-09.2010

J. Zhang, C. M. Petit, D. S. King, and A. L. Lee, Phosphorylation of a PDZ Domain Extension Modulates Binding Affinity and Interdomain Interactions in Postsynaptic Density-95 (PSD-95) Protein, a Membrane-associated Guanylate Kinase (MAGUK), Journal of Biological Chemistry, vol.286, issue.48, pp.41776-41785, 2011.
DOI : 10.1074/jbc.M111.272583

C. Faure, Calcineurin is essential for depolarization-induced nuclear translocation and tyrosine phosphorylation of PYK2 in neurons, Journal of Cell Science, vol.120, issue.17, pp.3034-3044, 2007.
DOI : 10.1242/jcs.009613

Y. Sun, A. Savanenin, P. H. Reddy, and Y. Liu, -Methyl-d-aspartate Receptors via Post-synaptic Density 95, Journal of Biological Chemistry, vol.276, issue.27, pp.24713-24718, 2001.
DOI : 10.1074/jbc.M103501200
URL : https://hal.archives-ouvertes.fr/inria-00100018

J. Fan, P38 MAPK is involved in enhanced NMDA receptor-dependent excitotoxicity in YAC transgenic mouse model of Huntington disease, Neurobiology of Disease, vol.45, issue.3, pp.999-1009, 2012.
DOI : 10.1016/j.nbd.2011.12.019

V. Brito, Neurotrophin receptor p75NTR mediates Huntington???s disease???associated synaptic and memory dysfunction, Journal of Clinical Investigation, vol.124, issue.10, pp.4411-4428, 2014.
DOI : 10.1172/JCI74809DS1
URL : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191006

A. Miguez, up-regulation and astrocyte-mediated inflammation, Human Molecular Genetics, vol.24, issue.17, pp.4958-4970, 2015.
DOI : 10.1093/hmg/ddv218

J. P. Vonsattel, Neuropathological Classification of Huntington??s Disease, Journal of Neuropathology and Experimental Neurology, vol.44, issue.6, pp.559-577, 1985.
DOI : 10.1097/00005072-198511000-00003

L. Mangiarini, Exon 1 of the HD Gene with an Expanded CAG Repeat Is Sufficient to Cause a Progressive Neurological Phenotype in Transgenic Mice, Cell, vol.87, issue.3, pp.493-506, 1996.
DOI : 10.1016/S0092-8674(00)81369-0

C. Faure, M. Ramos, and J. A. Girault, Pyk2 cytonuclear localization: mechanisms and regulation by serine dephosphorylation, Cellular and Molecular Life Sciences, vol.282, issue.22, pp.137-152, 2013.
DOI : 10.1007/s00018-012-1075-5

J. M. Van-raamsdonk, Z. Murphy, E. J. Slow, B. R. Leavitt, and M. R. Hayden, Selective degeneration and nuclear localization of mutant huntingtin in the YAC128 mouse model of Huntington disease, Human Molecular Genetics, vol.14, issue.24, pp.3823-3835, 2005.
DOI : 10.1093/hmg/ddi407

K. Prybylowski, The Synaptic Localization of NR2B-Containing NMDA Receptors Is Controlled by Interactions with PDZ Proteins and AP-2, Neuron, vol.47, issue.6, pp.845-857, 2005.
DOI : 10.1016/j.neuron.2005.08.016

P. J. Hallett, R. Spoelgen, B. T. Hyman, D. G. Standaert, and A. W. Dunah, Dopamine D1 Activation Potentiates Striatal NMDA Receptors by Tyrosine Phosphorylation-Dependent Subunit Trafficking, Journal of Neuroscience, vol.26, issue.17, pp.4690-4700, 2006.
DOI : 10.1523/JNEUROSCI.0792-06.2006

G. Köhr and P. Seeburg, Subtype-specific regulation of recombinant NMDA receptor-channels by protein tyrosine kinases of the src family., The Journal of Physiology, vol.492, issue.2, pp.445-452, 1996.
DOI : 10.1113/jphysiol.1996.sp021320

S. Taniguchi, Involvement of NMDAR2A tyrosine phosphorylation in depression-related behaviour, The EMBO Journal, vol.21, issue.23, pp.3717-3729, 2009.
DOI : 10.1038/634

M. Migaud, Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein, Nature, vol.396, pp.433-439, 1998.

C. Zhao, The Upregulation of NR2A-Containing N-Methyl-d-Aspartate Receptor Function by Tyrosine Phosphorylation of Postsynaptic Density 95 Via Facilitating Src/Proline-Rich Tyrosine Kinase 2 Activation, Molecular Neurobiology, vol.30, issue.2, pp.500-511, 2015.
DOI : 10.1007/s12035-014-8796-4

S. Yang, F. Roselli, A. V. Patchev, S. Yu, and O. Almeida, Non-receptor-tyrosine Kinases Integrate Fast Glucocorticoid Signaling in Hippocampal Neurons, Journal of Biological Chemistry, vol.288, issue.33, pp.23725-23739, 2013.
DOI : 10.1074/jbc.M113.470146
URL : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3745320

J. F. Sturgill, P. Steiner, B. L. Czervionke, and B. L. Sabatini, Distinct Domains within PSD-95 Mediate Synaptic Incorporation, Stabilization, and Activity-Dependent Trafficking, Journal of Neuroscience, vol.29, issue.41, pp.12845-12854, 2009.
DOI : 10.1523/JNEUROSCI.1841-09.2009
URL : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2787089

R. A. Frank, NMDA receptors are selectively partitioned into complexes and supercomplexes during synapse maturation, Nature Communications, vol.19, p.11264, 2016.
DOI : 10.1038/ncomms11264
URL : http://doi.org/10.1038/ncomms11264

S. Nada, Identification of PSD-93 as a Substrate for the Src Family Tyrosine Kinase Fyn, Journal of Biological Chemistry, vol.278, issue.48, pp.47610-47621, 2003.
DOI : 10.1074/jbc.M303873200

Y. Sato, Y. X. Tao, Q. Su, and R. A. Johns, Post-synaptic density-93 mediates tyrosine-phosphorylation of the N-methyl-d-aspartate receptors, Neuroscience, vol.153, issue.3, pp.700-708, 2008.
DOI : 10.1016/j.neuroscience.2008.03.006

T. Tezuka, H. Umemori, T. Akiyama, S. Nakanishi, and T. Yamamoto, PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methyl-D-aspartate receptor subunit NR2A, Proc. Natl Acad. Sci. USA 96, pp.435-440, 1999.
DOI : 10.1016/S0896-6273(01)80049-0

J. M. Corsi, Autophosphorylation-independent and -dependent Functions of Focal Adhesion Kinase during Development, Journal of Biological Chemistry, vol.284, issue.50, pp.34769-34776, 2009.
DOI : 10.1074/jbc.M109.067280
URL : https://hal.archives-ouvertes.fr/inserm-00432666

X. Zhao, X. Peng, S. Sun, A. Y. Park, and J. L. Guan, Role of kinase-independent and -dependent functions of FAK in endothelial cell survival and barrier function during embryonic development, The Journal of Cell Biology, vol.328, issue.6, pp.955-965, 2010.
DOI : 10.1152/physiol.00001.2005

L. Bongiorno-borbone, The translocation of focal adhesion kinase in brain synaptosomes is regulated by phosphorylation and actin assembly, Journal of Neurochemistry, vol.275, issue.6
DOI : 10.1046/j.1471-4159.2002.00906.x

W. G. Regehr, Short-Term Presynaptic Plasticity, Cold Spring Harbor Perspectives in Biology, vol.4, issue.7, p.5702, 2012.
DOI : 10.1101/cshperspect.a005702
URL : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385958

R. S. Zucker, Short-Term Synaptic Plasticity, Annual Review of Neuroscience, vol.12, issue.1, pp.13-31, 1989.
DOI : 10.1146/annurev.ne.12.030189.000305

S. Yang, M. D. Santos, C. M. Tang, J. G. Kim, and S. Yang, A Postsynaptic Role for Short-Term Neuronal Facilitation in Dendritic Spines, Frontiers in Cellular Neuroscience, vol.9, p.224, 2016.
DOI : 10.3389/fncel.2015.00469

C. Bourgin, K. K. Murai, M. Richter, and E. B. Pasquale, The EphA4 receptor regulates dendritic spine remodeling by affecting ?1-integrin signaling pathways, The Journal of Cell Biology, vol.9, issue.7, pp.1295-1307, 2007.
DOI : 10.1038/sj.onc.1203304

Y. Shi, C. G. Pontrello, K. A. Defea, L. F. Reichardt, and I. M. Ethell, Focal Adhesion Kinase Acts Downstream of EphB Receptors to Maintain Mature Dendritic Spines by Regulating Cofilin Activity, Journal of Neuroscience, vol.29, issue.25, pp.8129-8142, 2009.
DOI : 10.1523/JNEUROSCI.4681-08.2009

L. Suo, H. Lu, G. Ying, M. R. Capecchi, and Q. Wu, Protocadherin clusters and cell adhesion kinase regulate dendrite complexity through Rho GTPase, Journal of Molecular Cell Biology, vol.4, issue.6, pp.362-376, 2012.
DOI : 10.1093/jmcb/mjs034

Y. Kinoshita, Role for NUP62 depletion and PYK2 redistribution in dendritic retraction resulting from chronic stress, Proc. Natl Acad. Sci. USA 111, pp.16130-16135, 2014.
DOI : 10.1093/bioinformatics/bth487

C. M. Gladding, Calpain and STriatal-Enriched protein tyrosine Phosphatase (STEP) activation contribute to extrasynaptic NMDA receptor localization in a Huntington's disease mouse model, Human Molecular Genetics, vol.21, issue.17, pp.3739-3752, 2012.
DOI : 10.1093/hmg/dds154

J. Xu, Striatal-enriched Protein-tyrosine Phosphatase (STEP) Regulates Pyk2 Kinase Activity, Journal of Biological Chemistry, vol.287, issue.25, pp.20942-20956, 2012.
DOI : 10.1074/jbc.M112.368654
URL : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375518

J. Xu, Inhibitor of the Tyrosine Phosphatase STEP Reverses Cognitive Deficits in a Mouse Model of Alzheimer's Disease, PLoS Biology, vol.16, issue.2, p.1001923, 2014.
DOI : 10.1371/journal.pbio.1001923.s015

P. Dourlen, Functional screening of Alzheimer risk loci identifies PTK2B as an in vivo modulator and early marker of Tau pathology, Molecular Psychiatry, vol.23, issue.6, p.59, 2016.
DOI : 10.1016/j.neurobiolaging.2005.12.002

A. Giralt, O. Carreton, C. Lao-peregrin, E. D. Martin, and J. Alberch, Conditional BDNF release under pathological conditions improves Huntington's disease pathology by delaying neuronal dysfunction, Molecular Neurodegeneration, vol.6, issue.1, p.71, 2011.
DOI : 10.1111/j.1460-9568.2005.03925.x
URL : http://doi.org/10.1186/1750-1326-6-71

J. W. Slot and H. J. Geuze, Cryosectioning and immunolabeling, Nature Protocols, vol.82, issue.10, pp.2480-2491, 2007.
DOI : 10.1038/nprot.2007.365

O. Prange, T. P. Wong, K. Gerrow, Y. T. Wang, and A. El-husseini, A balance between excitatory and inhibitory synapses is controlled by PSD-95 and neuroligin, Proc. Natl Acad. Sci. USA 101, pp.13915-13920, 2004.
DOI : 10.1034/j.1601-183X.2003.00037.x

C. Y. Shao, R. Sondhi, P. S. Van-de-nes, and T. C. Sacktor, PKM?? is necessary and sufficient for synaptic clustering of PSD-95, Hippocampus, vol.24, issue.7, pp.1501-1507, 2012.
DOI : 10.1002/hipo.20996

O. Engmann, DARPP-32 interaction with adducin may mediate rapid environmental effects on striatal neurons, Nature Communications, vol.102, p.10099, 2015.
DOI : 10.1038/ncomms10099
URL : https://hal.archives-ouvertes.fr/hal-01317531