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Cadherin- -catenin Adhesion Complexes in Synaptic Development and Remodeling

Cadherin- -catenin Adhesion Complexes in Synaptic Development and Remodeling. Shernaz X. Bamji University of British Columbia 2006 NIDA Frontiers in Addiction Mini-Convention. Cadherin Superfamily. P. P. -cat. -cat. F-actin. Type II: VE-cad K-cad cad-8 to 12 cad-18 to 20 cad-24.

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Cadherin- -catenin Adhesion Complexes in Synaptic Development and Remodeling

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  1. Cadherin--catenin Adhesion Complexes in Synaptic Development and Remodeling Shernaz X. Bamji University of British Columbia 2006 NIDA Frontiers in Addiction Mini-Convention

  2. Cadherin Superfamily P P -cat -cat F-actin Type II: VE-cad K-cad cad-8 to 12 cad-18 to 20 cad-24 Type I: N-cad E-cad P-cad R-cad H-cad C-cad DE-cad V IV Seven-Pass Tm FAT-like III Protocadherin II I Desmosomal Classic VI Unique Fyn -cat DP DP T-cadherin -cat FAT-family flamingo starry night F-actin CNR-cadherin PCDH8/ arcadlin desmoglein desmocollin Adapted from : Angst et al., J.Cell Sci. 114:629

  3. Synaptic localization of cadherin and catenin PRESYNAPTIC active zone POSTSYNAPTIC Uchida et al. 1996. JCB. 135:767-779

  4. Synapse number and structure is altered in -catenin mutant mice -catenin mutant control 400 25 ** WT 20 MT 300 ** 15 synapses /1000 m2 vesicles / synapse 200 10 100 5 0 0 docked vesicle cluster WT MT

  5. / bassoon +/+ cadherin wnt signaling -catenin -catenin PDZ protein F-actin -/- Synaptic vesicles are diffusely localized when -catenin is ablated Synaptophysin-GFP +/+ -/- -/- 3 ** 2 Length of syn-GFP major axis (m) 1 0 -/- +/+

  6. What is the function of cadherin in synaptic plasticity?  Does regulation of cadherin--catenin interactions affect synaptic remodeling and plasticity?  What are the upstream regulators of cadherin--catenin interactions?

  7. There is an Increase in SV Cluster Splitting Following BDNF Treatment Rate : 1 frame/ 5 sec 2 m

  8. BDNF increases the density of synaptophysin-GFP puncta control Syn-GFP BDNF Syn-GFP

  9. cadherin -catenin Y654 -catenin PDZ protein F-actin BDNF mediates cadherin--catenin uncoupling IP: -catenin BDNF 10’ 30’ Ø P-tyr N-cadherin -catenin

  10. BDNF increases the frequency of synaptic vesicle cluster “splitting” and the density of synapses by disrupting cadherin- -catenin complexes BDNF BDNF BDNF ** 0.06 ** 0.05 200 0.04 Ave freq of splitting (synapse -1 X min -1) 150 0.03 Percent synapse density (Synaptophysin-GFP) 100 0.02 50 0.01 0 0 Y654F Syn-GFP Syn-GFP +Y654F Syn-GFP Syn-GFP

  11. Conclusions:  Cadherin/ -catenin adhesion complexes are important for localizing SVs to presynaptic compartments during development  Disruption of cadherin/ -catenin adhesion complexes is important for the formation of new synapses Hypothesis:  Weakening of cadherin/ -catenin complexes enhances synapse formation by increasing the mobility of SV clusters from existing synapses

  12. Synaptic vesicles associated with one synapse split to form new synapses and to associate with existing synapses Synaptophysin-PS-CFP Synaptophysin-RFP Synaptophysin-PS-CFP PSD-95

  13. Acknowledgements Louis F. Reichardt (University of California San Francisco San Francisco, CA) Shernaz X. Bamji Nikole Kimes Lucia Tapia Eileen Yoshida Yu Sun (University of British Columbia Vancouver, B.C.) Tula Foundation Michael Smith Foundation for Health Research Canadian Institutes of Heath Research (CIHR) Canadian Foundation for Innovation British Columbia Knowledge Development Fund

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