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

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

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

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

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

Centre for Synaptic Plasticity

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

Centre for Synaptic Plasticity Kei Cho Jihoon Jo Heon Seok

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

Centre for Synaptic Plasticity NCS-1 RNAi blocks mGluR-LTD but not NMDAR-LTD mGluR-LTDNMDAR-LTD Hz NCS-1 RNAi Luciferase RNAi D-AP ms 100 pA   1 1 Hz NCS-1 RNAi Control cells ms 100 pA    -gal NCS-1Merged  -gal + Luciferase-RNAi  -gal + NCS-1-RNAi Jo et al, (2008) Neuron. 60, Β-galNCS-1 Merged Luciferase RNAi NCS-1 RNAi

Centre for Synaptic Plasticity NCS-1 binds the BAR domain of PICK1 GST-PICK1 PDZ BAR GST-PICK GST-PICK1 full GST-PICK GST-PICK [Ca2+] free (  M) 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,

Centre for Synaptic Plasticity 5 Hz ms 100 pA 3 4 GST-BAR GST   D-AP ms 100 pA 3 4 GST-BAR GST   1 Hz The GST-BAR fusion protein blocks mGluR-LTD but not NMDAR-LTD mGluR-LTDNMDAR-LTD Jo et al, (2008) Neuron. 60, GST-BAR GST GST-BAR GST

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

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

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,

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,

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,

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for Synaptic Plasticity Hippocalcin RNAi and GFP-transfected hippocampal neurons LTP LTD Mascia Amici & Sheila Dargan, unpublished

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

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