neurotrophinneurotrophin-induced plasticity in the...
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Neurotrophin-induced plasticity in the developing visual system:
from axons and dendrites to synapses
NeurotrophinNeurotrophin--induced plasticity in the induced plasticity in the developing visual system: developing visual system:
from axons and dendrites to synapsesfrom axons and dendrites to synapses
Susana CohenSusana Cohen--Cory, Ph.D.Cory, Ph.D.Dept. of Neurobiology and BehaviorDept. of Neurobiology and BehaviorUniversity of California, IrvineUniversity of California, Irvine
1. Targeting2. Branching3. Synaptogenesis
1 2 3
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NeurotrophinsNeurotrophins and their receptorsand their receptors
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Neurotrophins can induce multiple actions and activate multiple signaling mechanisms
Neuronal survivalNeuronal survivalDifferentiationDifferentiationAxonal/Axonal/dendriticdendritic growthgrowthSynaptic Synaptic potentiationpotentiation/plasticity/plasticity
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BDNF signalingBDNF signaling((presynapticpresynaptic neuron)neuron)
↓↓ Synapse maturation & functionSynapse maturation & function
↓↓ Synapse stabilizationSynapse stabilization
↓↓ Arbor maturationArbor maturation
BDNF and the control of synaptic connectivityBDNF and the control of synaptic connectivity
↑↑ Synapse Synapse innervationinnervation densitydensity
↑↑ No. of postsynaptic partnersNo. of postsynaptic partners
↑↑ Exuberant axon arbor growthExuberant axon arbor growth
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IN VIVO ROLE IN VIVO ROLE –– ALTERING TARGET TISSUE INFLUENCEALTERING TARGET TISSUE INFLUENCE
Retina Optic TectumBDNFBDNF
TrkBTrkB
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P
M
Imaging Imaging presynapticpresynaptic sites in retinal axons sites in retinal axons in vivoin vivo
Yellow Yellow ==GFPGFP--synaptobrevinsynaptobrevin
++ DsRedDsRed((presynapticpresynaptic sites)sites)
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GFPGFP--tagged synaptic markers localize to tagged synaptic markers localize to ultrastructurallyultrastructurally identifiedidentifiedsynapses in the tadpole optic synapses in the tadpole optic tectumtectum
AbAb--associatedassociatedgold particlesgold particles
GFPGFP--SybSyb ControlControl
**
**
Postsynaptic endingPostsynaptic ending
PresynapticPresynaptic terminalterminal****
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Manipulating BDNF levels in the optic Manipulating BDNF levels in the optic tectumtectumBDNFBDNF or or blocking antibodies to BDNFblocking antibodies to BDNF
BDNFBDNF ororantianti--BDNFBDNF
Time lapseTime lapse
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Synapses are formed and eliminated in actively branching axon arSynapses are formed and eliminated in actively branching axon arborsbors
AlsinaAlsina et al., Nature et al., Nature NeurosciNeurosci., 2001., 2001
Analysis of axon branch and Analysis of axon branch and presynapticpresynaptic site dynamicssite dynamics
2 hr
StableStable
AddedAdded
EliminatedEliminated
2 , 4, 6, 8, 24 hr2 , 4, 6, 8, 24 hr
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BDNF enhances RGC axon arbor complexity and synaptic numberBDNF enhances RGC axon arbor complexity and synaptic number
ControlControl
BDNFBDNF
AlsinaAlsina et al., Nature et al., Nature NeurosciNeurosci., 2001., 2001
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ControlBDNFAnti-BDNF
0-2 hr 0-4 hr 0-6 hr 0-24 hr0
50
100
150
200
250
300
350
Time interval
Bra
nch
Num
ber (
%)
0-2 hr 0-4 hr 0-6 hr 0-24 hr0
50
100
150
200
250
300
350
Time interval
pres
ynap
ticcl
uste
r num
ber (
%)
1 2 34
5
BDNF influences axon arbor branch numberBDNF influences axon arbor branch number……
……and synapse numberand synapse number
**** ******
********
****
****
****** ******
************ pp < 0.05< 0.05
pp < 0.005< 0.005p p < 0.0005< 0.0005
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Syna
ptic
clu
ster
nu
mbe
r / a
rbor
leng
th
Time interval
0-2 hr 0-4 hr 0-6 hr 0-24 hr
1.0
1.5
2.0
ControlControl
BDNFBDNF
BDNF increases synaptic BDNF increases synaptic innervationinnervation density per axon terminaldensity per axon terminal
Alsina et al., Nature Neurosci., 2001
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ControlControl
p
m
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Anti-BDNFAntiAnti--BDNFBDNF
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0h0h 2h2h 4h4h
GFP-Syb 10 µm
Neutralizing endogenous BDNF with blocking antibodies promotes Neutralizing endogenous BDNF with blocking antibodies promotes axon branch and synapse eliminationaxon branch and synapse elimination
((HuHu, , NikolakopoulouNikolakopoulou and Cohenand Cohen--Cory, Development 2005)Cory, Development 2005)
Anti-BDNFAnti-BDNF
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PresynapticPresynaptic sites are destabilized and eliminated in the absence of BDNFsites are destabilized and eliminated in the absence of BDNF
ControlAnti-BDNF
0-2 2-4 4-6 6-8 8-240
25
50
75
100
Time interval (hours)
Stab
le a
xon
bran
ches
** ** **
0-2 2-4 4-6 6-8 8-240
25
50
75
100
Time interval (hours)
Stab
le p
resy
napt
iccl
uste
rs(%
)
**
******
**** ****
2 hr2 hr
2 hr2 hr
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BDNF increases axon arbor complexity by promoting branching BDNF increases axon arbor complexity by promoting branching and growth. and growth.
BDNF increases the density of synaptic BDNF increases the density of synaptic innervationinnervation per axon per axon terminal.terminal.
Neutralizing endogenous BDNF induces synapse disassemblyNeutralizing endogenous BDNF induces synapse disassemblyand axon branch elimination.and axon branch elimination.
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TectalTectal neuronsneurons
BDNFBDNFGFPGFP--TrkB.T1TrkB.T1
RFPRFP--synaptobrevinsynaptobrevin(eye (eye lipofectionlipofection))
Are the effects of BDNF direct on Are the effects of BDNF direct on presynapticpresynaptic terminal axons?terminal axons?
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Truncated TrkB.T1 acts as a dominant negative receptorTruncated TrkB.T1 acts as a dominant negative receptor
TrkB.FL
TK domainTK domain
TrkB.T1
Signal no signal
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GFPGFP--TrkB.T1 expressing optic axons project appropriately to TrkB.T1 expressing optic axons project appropriately to the optic the optic tectumtectum in cellin cell--specific transgenic tadpolesspecific transgenic tadpoles
MarshakMarshak et al., J. Neuroscience 2007et al., J. Neuroscience 2007
GFPGFP-- TrkB.T1TrkB.T1under under AchRAchR promoterpromoter
Transgenic Xenopus embryos Transgenic Xenopus tadpole
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GFPGFP--TrkB.T1TrkB.T1GFPGFP--controlcontrol
Altering Altering TrkBTrkB signaling influences axon growth cone morphology signaling influences axon growth cone morphology at the targetat the target
branched
gc
bran
ched
growthcone
GFPGFP--TrkB.T1TrkB.T1GFPGFP--controlcontrol
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Branched RGC axons expressing GFPBranched RGC axons expressing GFP--TrkB.T1 retain growth coneTrkB.T1 retain growth cone--like structures and develop few like structures and develop few presynapticpresynaptic sitessites
GFPGFP--controlcontrol GFPGFP--TrkB.T1TrkB.T1
*
RFPRFP--sybsyb RFPRFP--sybsyb
MarshakMarshak et al., J. Neuroscience 2007et al., J. Neuroscience 2007
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Expression of GFPExpression of GFP--TrkB.T1 in TrkB.T1 in RGCsRGCs results in simpler axon arborsresults in simpler axon arborswith high branch turnover rates with high branch turnover rates
MarshakMarshak et al., J. Neuroscience 2007et al., J. Neuroscience 2007
StableAddedEliminatedAdded and then eliminated
PresynapticPresynaptic site densitysite density
2h 4h 8h 24h6h
** ** ** ** **
0.00
0.25
0.50
0.75
1.00
1.25
Syna
ptic
den
sity
(clu
ster
s pe
r 10μ
m)
Branch dynamicsBranch dynamicsGFP- Control
GFP-TrkB.T1
Cha
nges
in b
ranc
h nu
mbe
r(e
very
2 h
ours
)
** **
Control
TrkB.T10
20
40
60
80
100
Control
TrkB.T1
StableStable AddedAdded
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BDNF/BDNF/TrkBTrkB
RGCsRGCsRGCs
TectalTectal neuronsneurons
Cell autonomous Cell autonomous TrkBTrkB signaling in signaling in RGCsRGCs modulates modulates the establishment of the establishment of retinotectalretinotectal synaptic connectivitysynaptic connectivity
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Expression of GFPExpression of GFP--TrkB.T1 in single RGC axons alters TrkB.T1 in single RGC axons alters synaptic vesicle number at synaptic vesicle number at retinotectalretinotectal synapsessynapses
GFPGFP--controlcontrol
GFPGFP--TrkB.T1TrkB.T1
500nm
70.8 70.8 ±± 6.166.16Synaptic vesicle poolSynaptic vesicle pool
48.3 48.3 ±± 5.01 5.01 **Synaptic vesicle poolSynaptic vesicle pool
Docked vesiclesDocked vesicles6.4 6.4 ±± 0.460.46
Docked vesiclesDocked vesicles3.9 3.9 ±± 0.59 0.59 **
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Imaging postsynaptic sites in Imaging postsynaptic sites in tectaltectal neuron neuron dendriticdendritic arbors arbors in vivoin vivo
Yellow Yellow ==PSDPSD--9595--GFPGFP++ DsRedDsRed
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ControlControl
0 hrs 24 hrsAntiAnti--BDNFBDNF
Blocking endogenous BDNF inducesBlocking endogenous BDNF inducespostsynaptic site eliminationpostsynaptic site elimination
(Sanchez et al, Development, 2006)(Sanchez et al, Development, 2006)
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BDNF influences postsynaptic site number by 24 hoursBDNF influences postsynaptic site number by 24 hoursbut does not alter but does not alter dendriticdendritic branchingbranching
PSDPSD--9595--GFP GFP punctapuncta
ControlBDNFAnti-BDNF
0
50
100
150
200
250
300
350
**
**
****
**
Time interval0-4h 0-24h 0-48h
tota
l PSD
95-G
FP p
unct
a(%
of i
nitia
l)
(Sanchez et al, Development, 2006)(Sanchez et al, Development, 2006)
Total branchesTotal branches Total lengthTotal length
0
50
100
150
200
250
300
350
Time interval0-4h 0-24h 0-48h
tota
l bra
nche
s (%
of i
nitia
l)
0
50
100
150
200
250
300
350
**
Time interval0-4h 0-24h 0-48h
tota
l len
gth
(% o
f ini
tial )
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BDNF increases synaptic BDNF increases synaptic innervationinnervation density in density in tectaltectalneuron neuron dendriticdendritic terminalsterminals
BDNFControl
0-4 hr 00--24 hr24 hr 0-48 hr
post
syna
ptic
clu
ster
nu
mbe
r / a
rbor
leng
th
Time interval
1.0
1.5
2.0
Postsynaptic Postsynaptic tectaltectalneuronneuron
pres
ynap
ticcl
uste
r nu
mbe
r / a
rbor
leng
th
Time interval
0-2 hr 0-4 hr 00--6 hr6 hr 0-24 hr
1.0
1.5
2.0
PresynapticPresynaptic retinal ganglionretinal ganglioncell axon arborcell axon arbor
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TectalTectal neuronsneurons
BDNFBDNF
Imaging Imaging dendriticdendritic morphology and synaptic specializationsmorphology and synaptic specializationsin in tectaltectal neurons with altered neurons with altered TrkBTrkB signalingsignaling
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GFPGFP--controlcontrol GFPGFP--TrkB.T1TrkB.T1
MarshakMarshak et al., J. Neuroscience 2007et al., J. Neuroscience 2007
SNAPSNAP--2525immunostainingimmunostaining
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GFP-Control
GFP-TrkB.T1
Control TrkB.T10
10
20
Den
drite
mot
ility
rate
(%± s
.e.m
.)
TrkB.T1Control0
1
2
3
Syna
ptic
den
sity
(SN
AP-
25 c
lust
ers
/10μ
m)
0h 24h 48h0
1
2
Den
driti
cco
mpl
exity
inde
x
Altering Altering TrkBTrkB signaling in signaling in tectaltectal neurons does not influenceneurons does not influencedendrite branch dynamics or synapse densitydendrite branch dynamics or synapse density
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BDNF
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SingleSingle--cell manipulations in cell manipulations in TrkBTrkB signalingsignalingCellCell--autonomous autonomous TrkBTrkB signaling influences axon arbor shape signaling influences axon arbor shape and synaptic site stability. and synaptic site stability. TrkBTrkB--mediated changes at synapses mediated changes at synapses can significantly affect synaptic function (EM observations can significantly affect synaptic function (EM observations ––decreased synaptic vesicle number). decreased synaptic vesicle number).
Confirm antiConfirm anti--BDNF effectsBDNF effects
Support Support BDNFBDNF’’ss potential to rescue developing circuits with potential to rescue developing circuits with altered activity or after injuryaltered activity or after injury
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Sonia Sonia MarshakMarshakMargarita Margarita MeynardMeynardMariangelaMariangela NikolakopoulouNikolakopoulou
Supported by:Supported by:National Eye InstituteNational Eye Institute
BertaBerta AlsinaAlsinaThuyThuy VuVuBing Bing HuHuAnalizaAnaliza SanchezSanchezSanaSana JavedJavedBen MatthewsBen Matthews