Learning and memory involves changes in the molecular machinery of synapses. AMPA receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the brain, and plasticity at excitatory synapses involves alterations in the number of AMPARs localised at the synaptic plasma membrane, brought about by regulated receptor trafficking.
AMPAR expression at the synaptic plasma membrane is regulated by endocytosis, exocytosis, recycling and lateral diffusion events that contribute to reductions (Long Term Depression, LTD) or increases (Long Term Potentiation, LTP) in synaptic strength. A number of proteins interact with AMPAR subunits and tightly regulate these trafficking events.
A major focus of my lab is investigating how these interacting proteins influence basic cell biological processes to bring about changes in AMPAR trafficking and hence synaptic strength. In particular, we are studying a protein called PICK1, which binds GluA2/3 subunits of AMPARs, and is involved in AMPAR internalisation and LTD.
One of the current projects in the lab is investigating the functional interaction between PICK1 and the machinery that regulates actin polymerisation. We recently showed that PICK1 inhibits Arp2/3-mediated actin polymerisation, and that this is required for NMDA-stimulated AMPAR internalisation and LTD (Rocca et al., 2008; see figure 1). We are now studying the upstream signaling pathways that modulate this inhibition.
In another project, we are studying AMPAR trafficking events that occur in an in vitro model of ischaemia (stroke). We believe that these trafficking events have certain features in common with LTD/LTP, and we have recently demonstrated that PICK1 regulates GluA2 trafficking during oxygen/glucose deprivation of hippocampal neurons (Dixon et al., 2009).
In addition to AMPAR number, synaptic strength correlates with the size of dendritic spines, which are the tiny protrusions on the dendrites of neurons that house the postsynaptic specialisation. They act to compartmentalise both the machinery and the biochemical signals that underlie synaptic transmission, providing a mechanism to ensure synapse-specificity for transmission and plasticity (see figure 2).
We are studying the molecular mechanisms that underlie changes in spine size during synaptic plasticity, and we are interested in how regulation of AMPAR trafficking may be linked to the regulation of spine morphology.
Kai Murk, Raj Halemani, Anna Antoniou, Elena Blanco Suarez, Louisa Cockbill.
Jaafari N, Henley JM, Hanley, JG. (2012) PICK1 mediates transient synaptic expression of GluA2-lacking AMPARs during glycine-induced AMPA receptor trafficking. Journal of Neuroscience. 34: 11618-11630.
Nakamura Y, Wood CL, Patton AP, Jaafari N, Henley JM, Mellor JR, Hanley JG. (2011) PICK1 inhibition of the Arp2/3 complex controls dendritic spine size and synaptic plasticity. EMBO Journal. 30: 719-730.
Dixon RM, Mellor JR, Hanley JG. (2009) PICK1-Mediated Glutamate Receptor Subunit 2 (GluR2) Trafficking Contributes To Cell Death In Oxygen/Glucose Deprived Hippocampal Neurons. Journal of Biological Chemistry. 284: 14230-14235.
Rocca DL, Martin S, Jenkins EL, Hanley JG. (2008) Inhibition of Arp2/3-mediated actin polymerisation by PICK1 regulates neuronal morphology and AMPA receptor endocytosis. Nature Cell Biology. 10: 259-271.