Cadherin--catenin Adhesion Complexes in Synaptic Development and Remodeling

Shernaz X. BamjiUniversity of British Columbia

2006 NIDA Frontiers in Addiction Mini-Convention

Cadherin Superfamily

DesmosomalD

P

Protocadherin

Fyn

Seven-Pass Tm

flamingostarry night

de

smo

colli

n

de

smo

gle

in

CN

R-c

ad

he

rin

PC

DH

8/

arc

ad

lin

FAT-family

DP

T-cadherin

FAT-like

Unique

ClassicI II

III

IV V

VI

Adapted from : Angst et al., J.Cell Sci. 114:629

F-actin

-cat-cat

Type I:N-cadE-cadP-cadR-cadH-cadC-cadDE-cad

Type II:VE-cadK-cadcad-8 to 12cad-18 to 20cad-24

F-actin

-cat-catP

P

active zone

PRESYNAPTIC

POSTSYNAPTIC

Uchida et al. 1996. JCB. 135:767-779

Synaptic localization of cadherin and catenin

control -catenin mutant

vesi

cles

/ sy

nap

se

0

5

10

15

20

25

**

WTMT

docked vesicle cluster

Synapse number and structure is altered in -catenin mutant mice

syn

ap

ses

/1000

m

2

WT MT0

100

200

300

400**

Synaptic vesicles are diffusely localized when -catenin is ablated

Synaptophysin-GFP

+/+ -/-

Leng

th o

f sy

n-

GFP

majo

r axis

(

m)

0

1

2

3

**

+/+ -/-

-/-

/ bassoon

+/+ -/-cadherin

-catenin

-catenin

F-actin

PDZ protein

wnt signaling

Does regulation of cadherin--catenin interactions affect synaptic remodeling and plasticity?

What are the upstream regulators of cadherin--catenin interactions?

What is the function of cadherin in synaptic plasticity?

Rate : 1 frame/ 5 sec 2 m

There is an Increase in SV Cluster Splitting Following BDNF Treatment

Syn-GFP

Syn-GFP

control

BDNF

BDNF increases the density of synaptophysin-GFP puncta

BDNF mediates cadherin--catenin uncoupling

cadherin

-catenin

-catenin

F-actin

PDZ protein

Y654

BDNF Ø 10’ 30’

IP: -catenin

P-tyr

N-cadherin

-catenin

BDNF increases the frequency of synaptic vesicle cluster “splitting” and the density of synapses by disrupting cadherin- -catenin complexes

0

50

100

150

200 **

BDNF

Syn

-GF

P

Syn

-GF

P

+Y

654F

Per

cent

syn

apse

den

sity

(Syn

apto

phys

in-G

FP

)0

0.05

0.04

0.02

0.01

Y65

4F

0.06

0.03

Ave

freq

of s

plitt

ing

(syn

apse

-1 X

min

-1)

Syn

-GF

P

Syn

-GF

P

BDNF

**

BDNF

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

QuickTime™ and aPhoto - JPEG decompressor

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Synaptic vesicles associated with one synapse split to form new synapses and to associate with existing synapses

Synaptophysin-PS-CFPPSD-95

Synaptophysin-PS-CFPSynaptophysin-RFP

Acknowledgements

Louis F. Reichardt

(University of California San FranciscoSan Francisco, CA)

Nikole Kimes

Shernaz X. Bamji

Lucia TapiaEileen Yoshida

Yu Sun

(University of British ColumbiaVancouver, B.C.)

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

Tula FoundationMichael Smith Foundation for Health ResearchCanadian Institutes of Heath Research (CIHR)Canadian Foundation for InnovationBritish Columbia Knowledge Development Fund