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Palmitoylation of δ-catenin by DHHC5 mediates activity-induced synapse plasticity

Abstract

Synaptic cadherin adhesion complexes are known to be key regulators of synapse plasticity. However, the molecular mechanisms that coordinate activity-induced modifications in cadherin localization and adhesion and the subsequent changes in synapse morphology and efficacy remain unknown. We demonstrate that the intracellular cadherin binding protein δ-catenin is transiently palmitoylated by DHHC5 after enhanced synaptic activity and that palmitoylation increases δ-catenin–cadherin interactions at synapses. Both the palmitoylation of δ-catenin and its binding to cadherin are required for activity-induced stabilization of N-cadherin at synapses and the enlargement of postsynaptic spines, as well as the insertion of GluA1 and GluA2 subunits into the synaptic membrane and the concomitant increase in miniature excitatory postsynaptic current amplitude. Notably, context-dependent fear conditioning in mice resulted in increased δ-catenin palmitoylation, as well as increased δ-catenin–cadherin associations at hippocampal synapses. Together these findings suggest a role for palmitoylated δ-catenin in coordinating activity-dependent changes in synaptic adhesion molecules, synapse structure and receptor localization that are involved in memory formation.

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Figure 1: δ-catenin palmitoylation and its association with synaptic N-cadherin are increased after activity.
Figure 2: Palmitoylation of δ-catenin occurs at C960 and C961 and requires K581 for binding to N-cadherin.
Figure 3: δ-catenin palmitoylation is required for activity-induced stabilization of N-cadherin within dendritic spine heads.
Figure 4: δ-catenin palmitoylation is required for activity-induced spine remodeling.
Figure 5: δ-catenin palmitoylation is required for activity-induced AMPA receptor insertion and changes in mEPSCs.
Figure 6: Context-dependent fear conditioning increases δ-catenin palmitoylation and N-cadherin associations in the hippocampus.
Figure 7: DHHC5 and DHHC20 palmitoylate δ-catenin, but activity-induced recruitment of δ-catenin to N-cadherin is mediated by DHHC5.
Figure 8: DHHC5 is required for activity-induced palmitoylation of δ-catenin and surface AMPAR insertion.

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Acknowledgements

This work was supported by Canadian Institutes of Health Research grants MOP-81158 (S.X.B.), MOP-81144 (S.X.B.), MOP-102617 (S.L.B.) and MOP-119347 (A.J.M.). The Centre for Applied Neurogenetics is funded by the Canada Excellence Research Chair Program and the Leading Edge Endowment Fund. We thank A. El-Husseini (University of British Columbia), C.-Y. Tai (Academica Sinica), M. Ehlers (Duke University) and R. Huganir (Johns Hopkins University) for their kind gifts of cDNA constructs. We are grateful to S. Jung, B. Jovellar and B. Santyr for technical assistance on the project.

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Authors

Contributions

G.S.B. designed the project, conducted biochemistry, imaging and behavioral experiments and conducted data analysis. Y.S. generated mutant cDNA constructs and conducted biochemistry and imaging experiments and data analysis. M.M. conducted imaging experiments and data analysis. D.B.-K. and K.P. conducted electrophysiology experiments that were designed and supervised by S.L.B. and A.J.M. S.X.B. designed and supervised the project. G.S.B. and S.X.B. wrote the paper.

Corresponding author

Correspondence to Shernaz X Bamji.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Acute increases in neuronal activity enhances PSD-95 palmitoylation and homeostatic increases in neuronal activity enhances δ-catenin palmitoylation.

14-16 DIV hippocampal neurons were (a,b) treated with a glycine solution for the indicated time, or (c,d) TTX for 48 h and lysates immunoprecipitated with the indicated antibodies. ABE chemistry and western blotting for streptavidin-HRP was used to determine palmitoylation of immunoprecipitated proteins. Omission of hydroxylamine (NH2OH) was used to control for non-specific incorporation of biotin. (a,b) In contrast to the time-course for δ-catenin palmitoylation shown in Fig. 1c,d, PSD-95 palmitoylation peaked 180 min after glycine treatment (n=3, p=0.012, F3,8=7.05). (c,d) δ-catenin palmitoylation was increased 48 h after treatment with TTX. (n=4, p=0.01, F2,9=15.17). Graphs represent mean ± SEM. The n value indicates the number of separate blots from separate cultures. *p<0.05, **p<0.01, one-way ANOVA, Tukey's test post hoc.

Supplementary Figure 2 Activity enhances the clustering of δ-catenin with surface N-cadherin at the postsynaptic membrane.

(a-d) Confocal images of 14 DIV neurons transfected with GFP-δ-catenin and N-cadherin-RFP before and 20, 40 and 180 min after (a,b,e) glycine or (c,d) glycine+AP5. (a,b) Glycine enhanced the IntDen of δ-catenin (GFP-δ-catenin: n=19, p<0.001, F3,18=15.79; N-cadherin-RFP: n=19, p=0.953, F3,18=60.91). Glycine+AP5 did not affect (c) puncta area (GFP-δ-catenin: n=9, p=0.446, F3,8=4.74; N-cadherin-RFP: n=9, p=0.105, F3,8=41.53) or (d) IntDen (GFP-δ-catenin: n=9, p=0.429, F3,8=41.29; N-cadherin-RFP: n=9, p=0.631, F3,8=76.03). Scale bar = 5μm.(e) Activity increased the colocalization of GFP-δ-catenin with PSD-95, 40 min after glycine (n=21 cells, 3 separate cultures; p=0.003, student's t-test). (g-l) 14-16 DIV hippocampal neurons were incubated with a glycine solution for the indicated amount of time and lysates immunoprecipitated with the indicated antibodies. (g,h) 40 min after glycine treatment, the amount of N-cadherin associated with δ-catenin was increased (n=3, p=0.034). (i,j) δ-catenin/N-cadherin interactions were enhanced 40 min following glycine treatment and maintained for 180 min (n=4, p=0.041, F3,12=7.61). (h,l) Following incubation with glycine for the indicated times, neurons were biotinylated with Sulfo-NHS-SS-biotin, and lysates immunoprecipitated with neutravidin-coated beads to isolate all surface proteins. There was an increase in the amount of δ-catenin associated with surface proteins 40 and 180 min after glycine treatment, (n=3, p=0.008, F4,10=6.35). In contrast, there was no change in the association of p120ctn with the surface fraction (n=3, p=0.958, F4,10=0.151) or the amount of N-cadherin at the membrane (n=3, p=0.776, F4,10=0.441). The n values indicate (a-e) the number of cells from 3 separate cultures, and (g-l) indicate the number of separate blots from separate cultures. All graphs represents mean ± SEM. (a-d) **p<0.01, repeated measures one-way ANOVA, Tukey's test post hoc. (e,h) *p<0.05, **p<0.01, student's t-test. (j,l)*p<0.05,; one-way ANOVA, Tukey's test post hoc.

Supplementary Figure 3 δ-catenin does not alter basal N-cadherin levels within spine heads and δ-catenin K581M and C960-1S do not impact N-cadherin stability.

(a-c) Hippocampal neurons were transfected at 10 DIV with the indicated constructs (*denotes shRNA-resistance) and fluorescence recovery after photoleaching (FRAP) determined at 15-16 DIV. (a) Fluorescence intensity of N-cadherin within spine heads before photobleaching was not impacted by expression of δ-catenin shRNA or δ-catenin constructs, nor by glycine treatment (n values indicated in Fig. 4, p=0.806, F12,140=0.639; one-way ANOVA). (b,c) Normalized fluorescence recovery of N-cadherin-RFP in cells expressing the indicated shRNAs and δ-catenin constructs. The dashed purple line represents the plateau for fluorescence recovery in control, untreated cells (Fig. 3c). (b) Points with error bars represent mean ± SEM, solid lines represent single exponential fit. Statistical tests compare plateau values from exponential fits ± SEM. The number of neurons used in each condition is indicated below, and represent cells obtained from at least 3 separate cultures: shRNA-c (n=11), shRNA-c + K581M (n=9), and shRNA-c + C960-1S (n=9); p=0.034, F2,26=3.85, one-way ANOVA, Tukey's test post hoc (no Tukey tests were significant). (c) The mobile fraction of N-cadherin-RFP (fluorescence within the ROI at the 5 min time point, normalized for photobleaching; mean ± SEM; p=0.897, F2,26=0.109; one-way ANOVA).

Supplementary Figure 4 Activity-induced insertion of AMPA receptors requires cadherin-binding and palmitoylation of δ-catenin.

(a) Confocal images of 15-16 DIV primary hippocampal neurons transfected at 10 DIV with SEP-GluA1 plus the indicated shRNA and RFP or RFP-δ-catenin constructs (*denotes shRNA resistance). SEP-fluorescent puncta are pseudocolored in heat maps. Cells were imaged before and 40-60 min after glycine treatment. Scale bar = 5μm. (b) IntDen of pre-existing SEP-GluA2 puncta following treatment with glycine or glycine+AP5, normalized to the mean IntDen of the same puncta before treatment (dashed line). n denotes the number of cells, and p values from paired t-tests as follows: shRNA-c (n=17, p<0.001), shRNA-c+AP5 (n=11, p=0.945), shRNA-c+WT (n=13, p=0.289), shRNA (n=9, p=0.158), shRNA+WT* (n=10, p=0.006), shRNA+K581M* (n=14, p=0.314), and shRNA+C960-1S* (n=11, p=0.056). (c) Percent colocalization of δ-catenin/GluA2 before, and 40 min after glycine treatment (p<0.001, F3,45=13.07; one-way ANOVA with Tukey's test post hoc). Crosshatches denote significance among “before” groups relative to shRNA+WT*, asterisks denote significance within groups before and after glycine. n denotes the number of cells, and p values paired t-tests within groups as follows: shRNA-c+WT (n=12, p=0.006), shRNA+WT* (n=13, p<0.001), shRNA+K581M* (n=12, p=0.763), and shRNA+C960-1S* (n=12, p=0.273). (d) IntDen of SEP fluorescence in cells expressing SEP-TfR-mCherry normalized to pre-existing SEP-fluorescent puncta before treatment (shRNA-c: n=7, p<0.001; shRNA-c+WT: n=7, p=0.002; shRNA: n=6, p=0.01). n=cells from at least 3 separate cultures. Graphs represent mean ± SEM. *p<0.05, **p<0.01, ***p<0.001; paired t-test. #p<0.05, ##p<0.01, one-way ANOVA with Tukey's test post hoc.

Supplementary Figure 5 DHHC5 and DHHC20 enhance the recruitment of δ-catenin to N-cadherin under basal conditions.

(a,b) Confocal images of hippocampal neurons transfected at 10 DIV with the indicated GFP-δ-catenin constructs, N-cadherin-RFP, and either an empty vector or the indicated Myc or HA-tagged DHHC constructs. Neurons were imaged at 14-16 DIV, 40 min after the indicated treatment with glycine or a control buffer lacking glycine. Scale bar = 20μm. (a) DHHC5 and DHHC20 are sufficient to cluster δ-catenin and enhance its colocalization with N-cadherin under basal conditions. Images for DHHC2 and DHHC8 are provided as negative controls. (b) Overexpression of DHHC5 and DHHC20 does not enhance the recruitment of palmitoylation-deficient (C960-1S) δ-catenin to N-cadherin clusters indicating that DHHC5 and DHHC20 enhance δ-catenin/N-cadherin colocalization by palmitoylating δ-catenin.

Supplementary Figure 6 Full length blots of those cropped and presented in the main figures.

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Brigidi, G., Sun, Y., Beccano-Kelly, D. et al. Palmitoylation of δ-catenin by DHHC5 mediates activity-induced synapse plasticity. Nat Neurosci 17, 522–532 (2014). https://doi.org/10.1038/nn.3657

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