1. 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 Plasticity Glutamate receptor and Synaptic Plasticity

2. Centre for Synaptic Plasticity Long term potentiation: the synaptic basis of memory Tim Bliss

3. Centre for Synaptic Plasticity Glutamate is the major excitatory neurotransmitter in the CNS and acts on four main sub-classes of receptor Jeff Watkins NMDA AMPA Kainate AMPAmGluKainate

4. Centre for Synaptic Plasticity Bi-directional synaptic plasticity: LTP and LTD long-term potentiation ( ) long-term depression ( ) InductionExpression Transduction

5. Centre for Synaptic Plasticity Bliss & Collingridge (1993) Nature 361, 31-39 AMPARs mediate low frequency excitatory synaptic transmission

6. Centre for Synaptic Plasticity

8. NMDARmGluR AMPAR NMDAR-LTD Two forms of LTD in the perirhinal cortex mGluR-LTD

9. Centre for Synaptic Plasticity Kei Cho Jihoon Jo Heon Seok

10. Centre for Synaptic Plasticity Inhibition of the PICK1-GluA2 interaction blocks mGluR-LTD but not NMDAR-LTD mGluR-LTDNMDAR-LTD 1 2 100 ms 100 pA 3 4 Pep2-EVKI Pep2-SVKE 121+2 3 4 3+4   1 Hz 5 Hz 1 2 100 ms 100 pA 3 4 Pep2-EVKI Pep2-SVKE 121+2 3 4 3+4   D-AP5 N C PICK1 GRIP NSF AP2 Jo et al, (2008) Neuron. 60, 1095-1111 Pep2-EVKI Pep2-SVKE Pep2-EVKI Pep2-SVKE

11. Centre for Synaptic Plasticity 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 21+2 343+4 100 ms 100 pA   1 1 Hz 2 3 4 NCS-1 RNAi Control cells 121+2 343+4 100 ms 100 pA    -gal NCS-1Merged  -gal + Luciferase-RNAi  -gal + NCS-1-RNAi Jo et al, (2008) Neuron. 60, 1095-1111 Β-galNCS-1 Merged Luciferase RNAi NCS-1 RNAi

12. Centre for Synaptic Plasticity NCS-1 binds the BAR domain of PICK1 GST-PICK1 PDZ 135 354 BAR 121 416 GST-PICK1 1-135 GST-PICK1 full GST-PICK1 354-416 GST-PICK1 121-354 [Ca2+] free (  M) 110 50 1001000 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

13. Centre for Synaptic Plasticity 5 Hz 1 2 100 ms 100 pA 3 4 GST-BAR GST   D-AP5 121+2 3 4 3+4 1 2 100 ms 100 pA 3 4 GST-BAR GST   1 Hz 1 21+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-BAR GST GST-BAR GST

14. Centre for Synaptic Plasticity mGluR- LTD in the perirhinal cortex Jo et al, (2008) Neuron. 60, 1095-1111

15. Centre for Synaptic Plasticity Bliss & Collingridge (1993) Nature 361, 31-39 AMPARs mediate low frequency excitatory synaptic transmission

16. Centre for Synaptic Plasticity PMT Simultaneous whole-cell recording and Ca 2+ imaging form neurons in slices Alford, Frenguelli et al, (1993) J. Physiol. 469, 693-716

17. Centre for Synaptic Plasticity PMT Simultaneous whole-cell recording and Ca 2+ imaging form neurons in slices Alford, Frenguelli et al, (1993) J. Physiol. 469, 693-716

18. Centre for Synaptic Plasticity Synaptic current Calcium transient 100 Hz, 1 s2 … Reveals NMDAR-induced transient Ca 2+ signals in dendritic spines Alford, Frenguelli et al, (1993) J. Physiol. 469, 693-716

19. Centre for Synaptic Plasticity Hippocalcin RNAi and GFP-transfected hippocampal neurons LTP LTD Mascia Amici & Sheila Dargan, unpublished

20. Centre for Synaptic Plasticity Activation of NMDARs results in internalisation of AMPARs Ashby et a.l (2004) J. Neurosci. 24; 5172 - 5176

21. Centre for Synaptic Plasticity Bliss & Collingridge (1993) Nature 361, 31-39 AMPARs mediate low frequency excitatory synaptic transmission