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Stability of dendritic spines and synaptic contacts is controlled by αN-catenin

Abstract

Morphological plasticity of dendritic spines and synapses is thought to be crucial for their physiological functions. Here we show that αN-catenin, a linker between cadherin adhesion receptors and the actin cytoskeleton, is essential for stabilizing dendritic spines in rodent hippocampal neurons in culture. In the absence of αN-catenin, spine heads were abnormally motile, actively protruding filopodia from their synaptic contact sites. Conversely, αN-catenin overexpression in dendrites reduced spine turnover, causing an increase in spine and synapse density. Tetrodotoxin (TTX), a neural activity blocker, suppressed the synaptic accumulation of αN-catenin, whereas bicuculline, a GABA antagonist, promoted it. Furthermore, excess αN-catenin rendered spines resistant to the TTX treatment. These results suggest that αN-catenin is a key regulator for the stability of synaptic contacts.

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Figure 1: Profiles of dendritic spines in Catna2+/+ and Catna2−/− neurons.
Figure 2: Enhanced motility in dendritic spines of Catna2−/− neurons.
Figure 3: Increased spine density in αN-catenin-overexpressing neurons.
Figure 4: Reduced turnover of dendritic spines in αN-catenin-overexpressing neurons.
Figure 5: Requirement of the C-terminal region of αN-catenin for the increase in spine density.
Figure 6: Effects of TTX and bicuculline on αN-catenin distribution and spine morphology in rat hippocampal neurons.

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References

  1. Ziv, N.E. & Smith, S.J. Evidence for a role of dendritic filopodia in synaptogenesis and spine formation. Neuron 17, 91–102 (1996).

    Article  CAS  Google Scholar 

  2. Jontes, J.D., Buchanan, J. & Smith, S.J. Growth cone and dendrite dynamics in zebrafish embryos: early events in synaptogenesis imaged in vivo. Nat. Neurosci. 3, 231–237 (2000).

    Article  CAS  Google Scholar 

  3. Okabe, S., Miwa, A. & Okado, H. Spine formation and correlated assembly of presynaptic and postsynaptic molecules. J. Neurosci. 21, 6105–6114 (2001).

    Article  CAS  Google Scholar 

  4. Marrs, G.S., Green, S.H. & Dailey, M.E. Rapid formation and remodeling of postsynaptic densities in developing dendrites. Nat. Neurosci. 4, 1006–1013 (2001).

    Article  CAS  Google Scholar 

  5. Dunaevsky, A., Tashiro, A., Majewska, A., Mason, C. & Yuste, R. Developmental regulation of spine motility in the mammalian central nervous system. Proc. Natl. Acad. Sci. USA 96, 13438–13443 (1999).

    Article  CAS  Google Scholar 

  6. Korkotian, E. & Segal, M. Regulation of dendritic spine motility in cultured hippocampal neurons. J. Neurosci. 21, 6115–6124 (2001).

    Article  CAS  Google Scholar 

  7. Lendvai, B., Stern, E.A., Chen, B. & Svoboda, K. Experience-dependent plasticity of dendritic spines in the developing rat barrel cortex in vivo. Nature 404, 876–881 (2000).

    Article  CAS  Google Scholar 

  8. Yuste, R. & Bonhoeffer, T. Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu. Rev. Neurosci. 24, 1071–1089 (2001).

    Article  CAS  Google Scholar 

  9. Tashiro, A., Minden, A. & Yuste, R. Regulation of dendritic spine morphology by the rho family of small GTPases: antagonistic roles of Rac and Rho. Cereb. Cortex 10, 927–938 (2000).

    Article  CAS  Google Scholar 

  10. Nakayama, A.Y., Harms, M.B. & Luo, L. Small GTPases Rac and Rho in the maintenance of dendritic spines and branches in hippocampal pyramidal neurons. J. Neurosci. 20, 5329–5338 (2000).

    Article  CAS  Google Scholar 

  11. Sala, C. et al. Regulation of dendritic spine morphology and synaptic function by Shank and Homer. Neuron 31, 115–130 (2001).

    Article  CAS  Google Scholar 

  12. Pak, D.T., Yang, S., Rudolph-Correia, S., Kim, E. & Sheng, M. Regulation of dendritic spine morphology by SPAR, a PSD-95-associated RapGAP. Neuron 31, 289–303 (2001).

    Article  CAS  Google Scholar 

  13. Hayashi, K. & Shirao, T. Change in the shape of dendritic spines caused by overexpression of drebrin in cultured cortical neurons. J. Neurosci. 19, 3918–3925 (1999).

    Article  CAS  Google Scholar 

  14. El-Husseini, A.E., Schnell, E., Chetkovich, D.M., Nicoll, R.A. & Bredt, D.S. PSD-95 involvement in maturation of excitatory synapses. Science 290, 1364–1368 (2000).

    CAS  PubMed  Google Scholar 

  15. Ethell, I.M. & Yamaguchi, Y. Cell surface heparan sulfate proteoglycan syndecan-2 induces the maturation of dendritic spines in rat hippocampal neurons. J. Cell Biol. 144, 575–586 (1999).

    Article  CAS  Google Scholar 

  16. Penzes, P. et al. Rapid induction of dendritic spine morphogenesis by trans-synaptic ephrinB-EphB receptor activation of the Rho-GEF kalirin. Neuron 37, 263–274 (2003).

    Article  CAS  Google Scholar 

  17. Passafaro, M., Nakagawa, T., Sala, C. & Sheng, M. Induction of dendritic spines by an extracellular domain of AMPA receptor subunit GluR2. Nature 424, 677–681 (2003).

    Article  CAS  Google Scholar 

  18. Fischer, M., Kaech, S., Wagner, U., Brinkhaus, H. & Matus, A. Glutamate receptors regulate actin-based plasticity in dendritic spines. Nat. Neurosci. 3, 887–894 (2000).

    Article  CAS  Google Scholar 

  19. Yamagata, M., Herman, J.P. & Sanes, J.R. Lamina-specific expression of adhesion molecules in developing chick optic tectum. J. Neurosci. 15, 4556–4571 (1995).

    Article  CAS  Google Scholar 

  20. Uchida, N., Honjo, Y., Johnson, K.R., Wheelock, M.J. & Takeichi, M. The catenin/cadherin adhesion system is localized in synaptic junctions bordering transmitter release zones. J. Cell Biol. 135, 767–779 (1996).

    Article  CAS  Google Scholar 

  21. Fannon, A.M. & Colman, D.R. A model for central synaptic junctional complex formation based on the differential adhesive specificities of the cadherins. Neuron 17, 423–434 (1996).

    Article  CAS  Google Scholar 

  22. Benson, D.L. & Tanaka, H. N-cadherin redistribution during synaptogenesis in hippocampal neurons. J. Neurosci. 18, 6892–6904 (1998).

    Article  CAS  Google Scholar 

  23. Huntley, G.W. & Benson, D.L. Neural (N)-cadherin at developing thalamocortical synapses provides an adhesion mechanism for the formation of somatopically organized connections. J. Comp. Neurol. 407, 453–471 (1999).

    Article  CAS  Google Scholar 

  24. Iwai, Y. et al. DN-cadherin is required for spatial arrangement of nerve terminals and ultrastructural organization of synapses. Mol. Cell. Neurosci. 19, 375–388 (2002).

    Article  CAS  Google Scholar 

  25. Togashi, H. et al. Cadherin regulates dendritic spine morphogenesis. Neuron 35, 77–89 (2002).

    Article  CAS  Google Scholar 

  26. Bozdagi, O., Shan, W., Tanaka, H., Benson, D.L. & Huntley, G.W. Increasing numbers of synaptic puncta during late-phase LTP: N-cadherin is synthesized, recruited to synaptic sites, and required for potentiation. Neuron 28, 245–259 (2000).

    Article  CAS  Google Scholar 

  27. Fischer, M., Kaech, S., Knutti, D. & Matus, A. Rapid actin-based plasticity in dendritic spines. Neuron 20, 847–854 (1998).

    Article  CAS  Google Scholar 

  28. Yu, X. & Malenka, R.C. β-catenin is critical for dendritic morphogenesis. Nat. Neurosci. 6, 1169–1177 (2003).

    Article  CAS  Google Scholar 

  29. Ebihara, T., Kawabata, I., Usui, S., Sobue, K. & Okabe, S. Synchronized formation and remodeling of postsynaptic densities: long-term visualization of hippocampal neurons expressing postsynaptic density proteins tagged with green fluorescent protein. J. Neurosci. 23, 2170–2181 (2003).

    Article  CAS  Google Scholar 

  30. Provost, E. & Rimm, D.L. Controversies at the cytoplasmic face of the cadherin-based adhesion complex. Curr. Opin. Cell Biol. 11, 567–572 (1999).

    Article  CAS  Google Scholar 

  31. Nagafuchi, A. Molecular architecture of adherens junctions. Curr. Opin. Cell Biol. 13, 600–603 (2001).

    Article  CAS  Google Scholar 

  32. Papa, M. & Segal, M. Morphological plasticity in dendritic spines of cultured hippocampal neurons. Neuroscience 71, 1005–1011 (1996).

    Article  CAS  Google Scholar 

  33. Trachtenberg, J.T. et al. Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature 420, 788–794 (2002).

    Article  CAS  Google Scholar 

  34. Grutzendler, J., Kasthuri, N. & Gan, W.B. Long-term dendritic spine stability in the adult cortex. Nature 420, 812–816 (2002).

    Article  CAS  Google Scholar 

  35. Matus, A. Actin-based plasticity in dendritic spines. Science 290, 754–758 (2000).

    Article  CAS  Google Scholar 

  36. Bek, S. & Kemler, R. Protein kinase CKII regulates the interaction of β-catenin with α-catenin and its protein stability. J. Cell Sci. 115, 4743–4753 (2002).

    Article  CAS  Google Scholar 

  37. Piedra, J. et al. p120-catenin-associated Fer and Fyn tyrosine kinases regulate β-catenin Tyr-142 phosphorylation and β-catenin-α-catenin interaction. Mol. Cell Biol. 23, 2287–2297 (2003).

    Article  CAS  Google Scholar 

  38. Murase, S., Mosser, E. & Schuman, E.M. Depolarization drives β-catenin into neuronal spines promoting changes in synaptic structure and function. Neuron 35, 91–105 (2002).

    Article  CAS  Google Scholar 

  39. Rimm, D.L., Koslov, E.R., Kebriaei, P., Cianci, C.D. & Morrow, J.S. α1(E)-catenin is an actin-binding and -bundling protein mediating the attachment of F-actin to the membrane adhesion complex. Proc. Natl. Acad. Sci. USA 92, 8813–8817 (1995).

    Article  CAS  Google Scholar 

  40. Itoh, M., Nagafuchi, A., Moroi, S. & Tsukita, S. Involvement of ZO-1 in cadherin-based cell adhesion through its direct binding to α-catenin and actin filaments. J. Cell Biol. 138, 181–192 (1997).

    Article  CAS  Google Scholar 

  41. Kussel-Andermann, P. et al. Vezatin, a novel transmembrane protein, bridges myosin VIIA to the cadherin-catenins complex. Embo J. 19, 6020–6029 (2000).

    Article  CAS  Google Scholar 

  42. Ackermann, M. & Matus, A. Activity-induced targeting of profilin and stabilization of dendritic spine morphology. Nat. Neurosci. 6, 1194–1200 (2003).

    Article  CAS  Google Scholar 

  43. Mizoguchi, A. et al. Nectin: an adhesion molecule involved in formation of synapses. J. Cell Biol. 156, 555–565 (2002).

    Article  CAS  Google Scholar 

  44. Maletic-Savatic, M., Malinow, R. & Svoboda, K. Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity. Science 283, 1923–1927 (1999).

    Article  CAS  Google Scholar 

  45. Engert, F. & Bonhoeffer, T. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature 399, 66–70 (1999).

    Article  CAS  Google Scholar 

  46. Hering, H. & Sheng, M. Dendritic spines: structure, dynamics and regulation. Nat. Rev. Neurosci. 2, 880–888 (2001).

    Article  CAS  Google Scholar 

  47. Nimchinsky, E.A., Sabatini, B.L. & Svoboda, K. Structure and function of dendritic spines. Annu. Rev. Physiol. 64, 313–353 (2002).

    Article  CAS  Google Scholar 

  48. Niwa, H., Yamamura, K. & Miyazaki, J. Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108, 193–199 (1991).

    Article  CAS  Google Scholar 

  49. Uchida, N. et al. Mouse αN-catenin: two isoforms, specific expression in the nervous system, and chromosomal localization of the gene. Dev. Biol. 163, 75–85 (1994).

    Article  CAS  Google Scholar 

  50. Hirano, S., Kimoto, N., Shimoyama, Y., Hirohashi, S. & Takeichi, M. Identification of a neural α-catenin as a key regulator of cadherin function and multicellular organization. Cell 70, 293–301 (1992).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank T. Manabe for TTX and H. Ishigami for maintaining the mice. This work was supported by the program Grants-in-Aid for Specially Promoted Research of the Ministry of Education, Science, Sports, and Culture of Japan to M.T.

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Correspondence to Masatoshi Takeichi.

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Supplementary information

Supplementary Fig. 1.

aN-catenin overexpression does not affect dendrite arborization. αN-cat-/- neurons were transfected with EGFP, and wild-type neurons, with either EGFP only or EGFP and αN-cat-flag at the time of plating. Dendrite branch analysis was performed at 7 DIV. In z-stacked images, the branches were traced manually by using LSM510 software; and TDBTN (total dendritic branch tip number), TDBL (total dendritic branch length), and ADBL (average dendritic branch length) were analyzed manually, according to the method described28. A total of 1026 branches in WT, 961 branches in αN-cat-/-, and 990 branches in αN-catenin-overexpressing neurons, obtained from 10 different neurons for each group, were analyzed. Data were compared by Student's t test. Histograms showing mean ± s.e.m. were constructed. (a) Normalized TDBTN in wild-type (WT), αN-cat-/-, and αN-catenin-overexpressing neurons. The raw data was 102.6 for WT, 96.1 for αN-cat-/-, and 99.0 for αN-catenin overexpression. There was no significant difference between WT and αN-cat-/- (P = 0.39) or between WT and aN-catenin-overexpressing neurons (P = 0.30) by Student's t test. (b) Normalized TDBL. The raw data was 1428.2 for WT, 1337.6 for αN-cat-/-, and 1405.5 for αN-catenin-overexpressing neurons. There was no significant difference between WT and αN-cat-/- (P = 0.44) or between WT and αN-catenin-overexpressing neurons (P = 0.29). (c) Normalized ADBL. The raw data was 14.0 for WT, 14.0 for αN-cat-/-, and 14.6 for aN-catenin-overexpressing neurons. There was no significant difference between WT and αN-cat-/- (P = 0.28) or between WT and αN-catenin-overexpressing neurons (P = 0.28). (GIF 7 kb)

Supplementary Video 1.

Time-lapse movie of an EGFP-tagged actin-transfected αN-cat+/+ neuron at 15 DIV. Images were acquired at 1-min intervals over a 95-min period. (MOV 2366 kb)

Supplementary Video 2.

Time-lapse movies of an EGFP-tagged actin-transfected αN-cat-/- neuron at 15 DIV. Images were acquired at 1-min intervals over a 95-min period. (MOV 2534 kb)

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Abe, K., Chisaka, O., van Roy, F. et al. Stability of dendritic spines and synaptic contacts is controlled by αN-catenin. Nat Neurosci 7, 357–363 (2004). https://doi.org/10.1038/nn1212

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