beyond our genetic destiny: we are our life’s experiences

Centre for Synaptic Plasticity

The human brain, a 3-pound mass of interwoven nerve cells determines our sensations, emotions, memory, intelligence, creativity, thought and action. It is the part of our anatomy that truly makes us who we are. It is more complex and versatile than any computer. Understanding how the brain works is one of the greatest challenges for science in the 21st century.

Beyond our genetic destiny: we are our life’s experiences

Centre for Synaptic Centre for Synaptic PlasticityPlasticity

Glutamate receptor and Synaptic Plasticity


Long term potentiation: the synaptic basis of memory

Tim Bliss


Glutamate is the major excitatory neurotransmitter in the CNS and acts on four main sub-classes of receptor

Jeff Watkins NMDA

AMPA

Kainate

AMPA mGluKainate


Bi-directional synaptic plasticity: LTP and LTD

long-term potentiation ( )

long-term depression ( )

Induction ExpressionTransduction


Bliss & Collingridge (1993) Nature 361, 31-39

AMPARs mediate low frequency excitatory synaptic transmission


NMDAR mGluR

AMPAR AMPAR

NMDAR-LTD

Two forms of LTD in the perirhinal cortex

mGluR-LTD


Kei ChoJihoon Jo Heon Seok


Inhibition of the PICK1-GluA2 interaction blocks mGluR-LTD but not NMDAR-LTD

mGluR-LTDNMDAR-LTD

1

2

100 ms

10

0 p

A

3

4

Pep2-EVKI

Pep2-SVKE

1 2 1+2

3 4 3+4

1 Hz5 Hz

1 2

100 ms

10

0 p

A

3

4

Pep2-EVKI

Pep2-SVKE

1 2 1+2

3 4 3+4

D-AP5

N

C

PICK1GRIP

NSFAP2

Jo et al, (2008) Neuron. 60, 1095-1111

Pep2-EVKIPep2-SVKE

Pep2-EVKIPep2-SVKE


NCS-1 RNAi blocks mGluR-LTD but not NMDAR-LTD

mGluR-LTDNMDAR-LTD

1 2

5 Hz

NCS-1 RNAi

Luciferase RNAi

D-AP5

3

4

1 2 1+2

3 4 3+4100 ms

10

0 p

A

1

1 Hz

23

4

NCS-1 RNAi

Control cells

1 2 1+2

3 4 3+4

100 ms1

00

pA

-gal NCS-1 Merged

-ga

l +Lu

cife

rase

-RN

Ai

-ga

l +

NC

S-1

-RN

Ai

Jo et al, (2008) Neuron. 60, 1095-1111

Β-gal NCS-1 Merged

Luciferase RNAi

NCS-1 RNAi


NCS-1 binds the BAR domain of PICK1

GST-PICK1PDZ

135 354

BAR

121 416

GST-P

ICK1

1-13

5

GST-PIC

K1 full

GST-PIC

K1 354

-416

GST-PIC

K1 121

-354

[Ca2+]free (M) 1 10 50 100 1000

NCS-1

PICK1

Ca sensitivity of NCS-1 and PICK1 interactions

Interactions between PICK1 and NCS-1

NCS-1

Jo et al, (2008) Neuron. 60, 1095-1111


5 Hz

12

100 ms

10

0 p

A

3

4

GST-BAR

GST

D-AP5

1 2 1+2

3 4 3+4

1

2

100 ms

10

0 p

A3

4

GST-BAR

GST

1 Hz

1 2 1+2

3 4 3+4

The GST-BAR fusion protein blocks mGluR-LTD but not NMDAR-LTD

mGluR-LTDNMDAR-LTD

Jo et al, (2008) Neuron. 60, 1095-1111

GST-BARGST GST-BAR

GST


mGluR- LTD in the perirhinal cortex

Jo et al, (2008) Neuron. 60, 1095-1111


PMTPMT

Simultaneous whole-cell recording and Ca2+ imaging form neurons in slices

Alford, Frenguelli et al, (1993) J. Physiol. 469, 693-716


Synaptic current

Calcium transient

100 Hz, 1 s2

… Reveals NMDAR-induced transient Ca2+ signals in dendritic spines

Alford, Frenguelli et al, (1993) J. Physiol. 469, 693-716


Hippocalcin RNAi and GFP-transfected hippocampal neurons

Time ( min )0 10 20 30

Nor

mal

ised

EP

SC

am

plitu

de

0

1

2

3

ab

LTP

LTD

Mascia Amici & Sheila Dargan, unpublished


Activation of NMDARs results in internalisation of AMPARs

Ashby et a.l (2004) J. Neurosci. 24; 5172 - 5176

beyond our genetic destiny: we are our life’s experiences

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