Drugs of abuse alter synaptic connections in the reward circuitry of the brain, which leads to long-lasting behavioral changes that underlie addiction. Here we show that cadherin adhesion molecules play a critical role in mediating synaptic plasticity and behavioral changes driven by cocaine. We demonstrate that cadherin is essential for long-term potentiation in the ventral tegmental area and is recruited to the synaptic membranes of excitatory synapses onto dopaminergic neurons following cocaine-mediated behavioral conditioning. Furthermore, we show that stabilization of cadherin at the membrane of these synapses blocks cocaine-induced synaptic plasticity, leading to a reduction in conditioned place preference induced by cocaine. Our findings identify cadherins and associated molecules as targets of interest for understanding pathological plasticity associated with addiction.
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We thank the UBC Bioimaging Facility for use of shared equipment for sample processing; S.B. Floresco for extensive discussion and comments on the manuscript; C.A. Winstanley, T.P. O'Connor, K. Haas and D.W. Allan for comments on the manuscript; and K. Goodwin for assistance with data analysis. This work was supported by grants from Canadian Institutes of Health Research MOP-130526 to S.X.B., and MOP-102617 and FDN-147473 to S.L.B.
The authors declare no competing financial interests.
Integrated supplementary information
(a) VTA inhibitory neurons co-immunostained for cadherins (green), GAD67 (magenta) and DAPI (blue). Scale bar = 10 μm. Quantification of the proportion of dopaminergic neurons (b) and GABAergic neurons (c) that were immunopositive for different classical cadherins (DAT+: n = 26, 39, 68, 23, 46 cells immunostained for N-cadherin, R-cadherin, cadherins -7, -8, and -11, respectively; GAD67+: n = 45, 23, 31, 26, 30 immunostained for N-cadherin, R-cadherin, cadherins -7, -8, and -11, respectively). Immunopositive cells were defined as cells in which the immunofluorescence signal for each cadherin was over 2.5 fold greater than average signal detected in secondary-only controls. (d-h) Quantification of somatic immunofluorescence signal levels for N-cadherin (n = 26 DAT+, 45 GAD67+ cells from 2 mice) (d), R-cadherin (n = 39 DAT+, 23 GAD67+ cells from 2 mice) (e), cadherin-7 (n = 68 DAT+, 31 GAD67+ cells from 2 mice) (f), cadherin-8 (n = 23 DAT+, 26 GAD67+ cells from 2 mice) (g) and cadherin 11 (n = 46 DAT+, 30 GAD67+ cells from 2 mice) (h) in DAT+, GAD67+ neurons and secondary-only controls (n = 23 DAT+, 18 GAD+ cells with anti-mouse secondary only; n = 75 DAT+, 50 GAD67+ cells with anti-rabbit secondary only) for each cell type. In all cell types (d-h), immunostaining levels for each of the cadherin isoforms were significantly greater than secondary-only controls (p<0.0001, 2-way ANOVA, significant main effect of immunostain condition, p<0.001, Bonferroni’s test post hoc) (i) Representative immunoblots identifying cadherins in the VTA. Sizes of cadherin isoforms detected were consistent with the predicted sizes of each protein (see Methods). (j) Full length immunoblots for cadherin isoforms. Representative Data shown as mean ± SEM with individual cells (circles) overlaid.
(a) Diagram of estimated sizes of immunogold reagents, and maximum distance from the synaptic membrane for immunogold particles recognizing target proteins. Empirical studies have shown that antibody-conjugated immunogold particles are localized to within 30 nm of target epitopes55. Cadherin: The maximum distance for immungold particles recognizing cadherin at the synaptic membrane is ~40 nm. The primary antibody recognizes a target epitope in the C-terminal tail, and a conservative estimate for the size of this tail is ~10 nm in length based on crystal structures of cadherin C-terminal tail co-crystallized with β-catenin56. GluA1: The maximum distance for immungold particles recognizing GluA1 at the synaptic membrane is ~30 nm; the primary antibody recognizes an extracellular fragment. GluA2: The maximum distance for immungold particles recognizing GluA2 at the synaptic membrane is ~35 nm; the primary antibody recognizes C-terminal tail fragment, and a conservative estimate of the size of this tail is ~5 nm, based on the length of the C-terminal tail sequence57. (b-d) Top: Representative images of immunolabelling at synapses in the VTA. Bottom: Histogram of immunogold-labelling from the synaptic membrane (n= >100 synapses). The specificity of GluA1 (B), GluA2 (C) and PSD-95 (D) labelling at postsynaptic densities validates the use of these antibodies. (e) Top: PSD-95 and gephyrin immunolabelling at synapses in the VTA. Gephyrin immunostaining is restricted to symmetric synapses whereas PSD-95 staining is restricted to asymmetric synapses. Bottom: The majority (>93%) of PSD-95 labelling was observed at asymmetric synapses that were not labelled by the inhibitory synapse marker, gephryin. This validates the identification of excitatory synapses through the use of PSD-95 labelling combined with asymmetric synapse morphology (n=4 mice, >150 synapses). (f) The dopamine transporter (DAT) antibody was validated by co-labeling with tyrosine hydroxlase (TH). Over 80% of cells in the VTA that were labelled with DAT also co-labelled for TH, indicating that the DAT antibody accurately identifies dopaminergic neurons (n=3 mice, >50 synapses). All scale bars = 100 nm. Data shown as mean ± SEM with individual mice (circles) overlaid.56. Huber, A.H. & Weis, W.I. The structure of the beta-catenin/E-cadherin complex and the molecular basis of diverse ligand recognition by beta-catenin. Cell 105, 391–402 (2001).57. Song, I. & Huganir, R.L. Regulation of AMPA receptors during synaptic plasticity. Trends Neurosci. 25, 578–588 (2002).
Supplementary Figure 3 Overall levels of cadherin and GluA1 at VTA synapses are unaffected by acquisition and extinction of CPP.
For each behavioral condition, the total number of immunogold-labelled target proteins (cadherin or GluA1) at synaptic compartments (within 500 nm of the synaptic membrane) were counted in saline and cocaine groups, and expressed as a percentage of the saline group. Total immunogold-labelled cadherin at excitatory synapses (a) and inhibitory synapses (b) were unchanged following cocaine-induced CPP, home cage administration of cocaine, extinction of CPP, following return to home cage for 6 days after CPP (‘CPP + HC’), or Food CPP (NF: No food, PF: Palatable food) (c) Total immunogold-labelled GluA1 at excitatory synapses was also unchanged following cocaine-induced CPP, home cage administration of cocaine, extinction of CPP, return to home cage during extinction period after conditioning or Food CPP. Two-way ANOVA, Data shown as mean ± SEM with individual mice (circles) overlaid.
Supplementary Figure 4 Time spent in cocaine-conditioned chamber is correlated with increased cadherin localized to the synaptic membrane at both pre- and postsynaptic compartments of excitatory synapses onto dopaminergic neurons in the VTA.
The percentage of cadherin localized to the synaptic membrane at excitatory synapses onto dopaminergic neurons in the VTA was significantly correlated with time spent in conditioned chamber following cocaine CPP in (a) presynaptic compartments (Linear regression, p<0.05, F(1,10) = 7.351), (b) postsynaptic compartments (Linear regression, p<0.05, F(1,10) = 5.143), and (c) both pre- and postsynaptic compartments analyzed together (Linear regression, p<0.01, F(1,22) = 13.44).
Supplementary Figure 5 No changes in localization of cadherin or GluA1 at synapses onto dopaminergic neurons in the VTA following home-cage administration of cocaine, extinction of cocaine CPP or return to home cage after CPP.
Following homecage administration of cocaine unpaired with a novel environment, no changes in the distribution of cadherin were observed at (a) excitatory synapses or (b) inhibitory synapses, and (c) no changes in the distribution of GluA1 was observed at excitatory synapses onto dopaminergic neurons in the VTA, compared with controls that received only saline. Following extinction of cocaine CPP by reintroduction to the test apparatus without further reinforcement with cocaine (see Fig. 2b, Day 13), no changes in the distribution of cadherin were observed at (d) excitatory synapses or (e) inhibitory synapses, and (f) no changes in the distribution of GluA1 was observed at excitatory synapses onto dopaminergic neurons in the VTA, compared with controls that received only saline. Following cocaine CPP and return to home cage for 6 days, no changes in the distribution of cadherin were observed at (g) excitatory synapses or (h) inhibitory synapses, and (i) no changes in the distribution of GluA1 was observed at excitatory synapses onto dopaminergic neurons in the VTA, compared with controls that received only saline. See also Fig. 2e, h, k for analysis of relative % of cadherin and GluA1 localized to synaptic membrane in each condition.
Supplementary Figure 6 Food CPP does not affect the localization of cadherin and GluA1 at VTA synapses.
(a) Experimental schedule for induction of food CPP. Pairing of palatable food with the conditioned chamber produced robust CPP (p<0.05, significant interaction between genotype and test day, two-way RM ANOVA, F(1,10) = 8.325, *p< 0.05, Bonferroni’s test post hoc, n=6 mice control and palatable food). (b,c) No changes in the distribution of cadherin were observed at (b) excitatory synapses or (c) inhibitory synapses. (d) No redistribution of GluA1 was observed at excitatory synapses onto dopaminergic neurons in the VTA. See also Fig. 2e, h, k ‘Food CPP’ for analysis of relative % of cadherin and GluA1 localized to synaptic membrane. Data shown as mean ± SEM.
Supplementary Figure 7 No changes in localization of cadherin at synapses onto nondopaminergic neurons in the VTA following cocaine CPP.
(a) Electron micrograph of VTA synapse showing immunogold-labelled GAD67, PSD-95 and cadherin (Scale bar = 100 nm). (b-c) No change in the localization of cadherin at excitatory (b) or inhibitory (c) synapses onto GAD67+ neurons was observed following cocaine CPP. The relative percentage of cadherin at the synaptic membrane at excitatory and inhibitory synapses ([#cadherin beads within 40 nm of the pre and postsynaptic membrane] / [# beads within 500 nm of the synaptic membrane], expressed as a percent relative to saline controls) was also unchanged compared to saline controls following cocaine CPP (unpaired t-tests, n = 3 mice). (d) Electron micrograph of VTA synapse showing immunogold-labelled VGLUT2, PSD-95 and cadherin (Scale bar = 100 nm). (e-f) No change in the localization of cadherin at excitatory (e) or inhibitory (f) synapses onto VGLUT2+ neurons was observed following cocaine CPP. The relative percentage of cadherin at the synaptic membrane at excitatory and inhibitory synapses was also unchanged compared to saline controls following cocaine CPP (unpaired t-tests, n = 3 mice. > 100 synapses were analyzed per condition). Data shown as mean ± SEM with individual mice (circles) overlaid.
Supplementary Figure 8 Increased cadherin and GluA1 localization to the synaptic membrane at individual synapses onto dopaminergic neurons in the VTA following cocaine CPP.
The proportion of GluA1 localized to the synaptic membrane was significantly higher in individual synapses with a greater proportion of cadherin localized to the synaptic membrane in (a) saline controls (p<0.0001 one-way ANOVA, F(2,8) = 71.57) and (b) following cocaine CPP (p<0.0001 one-way ANOVA, F(2,11) = 33.96) (c) Following cocaine CPP, a significantly smaller proportion of synapses in the VTA had ‘low’ cadherin localization to the synaptic membrane, while a significantly greater proportion of synapses had a ‘high’ cadherin localization to the synaptic membrane (p<0.0001, significant interaction between treatment and cadherin groups, two-way ANOVA, F(2,15) = 18.40). **p< 0.01, **p< 0.01, ***p< 0.001 Bonferroni’s test post hoc, n=3 mice saline, n=4 mice cocaine CPP. Data shown as mean ± SEM with individual mice (circles) overlaid.
No changes in consumption of low-fat food (a) or high-fat food (b) over a 24-hour period were observed in DAT-Cre;β-catΔex3 mice (unpaired t-tests, n=5 mice low-fat, 5 mice high-fat WT, n=6 mice low-fat, 5 mice high-fat DAT-Cre;β-catΔex3) indicating similar appetitive behavior. (c) At 4-6 weeks of age, no difference in average body weight was observed between age-matched DAT-Cre;β-catΔex3 mice and littermate controls (unpaired t-test, n=10 mice per group). Data shown as mean ± SEM with individual mice (circles) overlaid.
Supplementary Figure 10 No changes in DAT-Cre;β-catΔex3 mice of overall expression of Wnt targets in VTA dopamine neurons or levels of cadherin, GluA2 or GluA1 at VTA synapses.
(a) Representative images of immunostaining for Wnt targets in VTA dopaminergic neurons (DAT; dopamine transporter). No significant differences in Wnt target expression were observed dopaminergic neurons in of DAT-Cre;β-catΔex3 and control mice (Scale bar = 5 μm), indicating that the increase in β-catenin (a component of the Wnt signalling pathway) in DAT-Cre;β-catΔex3 mice did not result in alterations in Wnt signalling. This finding is consistent with our previous work demonstrating that stabilization of β-catenin in adult hippocampal neurons using this transgenic line did not result in increases in Wnt target mRNA or protein levels20 and evidence that differentiated neurons are less sensitive to fluctuations in cytoplasmic β-catenin levels58, which may be mediated by greater control of nuclear transport of β-catenin in neurons59. (b) Quantification of immunostaining for Wnt targets, no differences between groups were observed (two-way ANOVA, n=8, 12 (Axin2), n=9, 12 (Lef1), n=18, 13 (c-Jun), n=13, 9 (c-Myc) dopaminergic neurons from WT, DAT-Cre;β-catΔex3, respectively). No changes in total levels of immunogold-labelled cadherin (c), GluA2 (d) or GluA1 (e) were observed in DAT-Cre;β-catΔex3 mice and littermate controls under basal conditions or following cocaine CPP (cadherin: n=3 mice per condition, GluA2: n = 3 mice per condition, GluA1: n = 3 mice control saline, 3 mice control cocaine, 5 mice DAT-Cre;β-catΔex3 saline, 4 mice DAT-Cre;β-catΔex3 cocaine; >100 synapses per group). Two-way ANOVA, data shown as mean ± SEM with individual cells or mice (circles) overlaid.58. Kratz, J.E. et al. Expression of stabilized beta-catenin in differentiated neurons of transgenic mice does not result in tumor formation. BMC Cancer 2, 33 (2002).59. Schmeisser, M.J., Grabrucker, A.M., Bockmann, J. & Boeckers, T.M. Synaptic cross-talk between N-methyl-D-aspartate receptors and LAPSER1-beta-catenin at excitatory synapses. J. Biol. Chem. 284, 29146–29157 (2009).
Supplementary Figure 11 No changes in DAT-Cre;β-catΔex3 mice to morphology or density of VTA synapses.
(a) Representative images of VTA synapses in DAT-Cre;β-catΔex3 mice and littermate controls. No significant differences in synapse length (b) or synapse density (c) of excitatory or inhibitory synapses were observed between groups (two-way ANOVA, n= 3 mice per group). Data shown as mean ± SEM with individual mice (circles) overlaid.
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Mills, F., Globa, A., Liu, S. et al. Cadherins mediate cocaine-induced synaptic plasticity and behavioral conditioning. Nat Neurosci 20, 540–549 (2017). https://doi.org/10.1038/nn.4503
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