A major focus of the lab is investigating how basic cell biological processes interact with AMPAR subunits to bring about changes in AMPAR trafficking and hence synaptic strength. In particular, we are studying a PDZ- and BAR-domain protein called PICK1, which binds GluA2/3 subunits of AMPARs, and is involved in AMPAR internalisation and LTD. We have demonstrated that PICK1 inhibits Arp2/3-mediated actin polymerisation, and that this is required for NMDA-stimulated AMPAR internalisation and LTD (Rocca et al., 2008, Nat. Cell Biol; Nakamura et al., 2011, EMBO J.; Rocca et al., 2013, Neuron). We are also studying how PICK1 interacts with core components of the endocytic machinery to regulate clathrin-coated vesicle formation (Fiuza et al., 2017, J. Cell Biol.).
Increase in endogenous AMPAR internalisation in cultured hippocampal neurons in response to stimulation with NMDA.
Schematic representation of AMPAR trafficking pathways involved in LTD or LTP.
As well as “normal” plasticity, we are studying AMPAR trafficking events that occur in response to acute injury, such as mechanical injury (a model for traumatic brain injury, TBI) and oxygen/glucose deprivation (OGD; a model for ischaemia). Brain ischaemia occurs when the blood supply to the brain is interrupted, for example by occlusion following a stroke, or as a result of cardiac arrest. We are studying the specific endosomal sorting steps that are involved in regulating cell-surface AMPARs in response to OGD or TBI. The majority of AMPARs contain GluA2 subunit, and consequently are Ca2+ impermeable. OGD and TBI cause trafficking events that result in the loss of surface GluA2-containing AMPARs, and therefore an increase in Ca2+ permeable AMPARs, which contribute to neuronal death. We have discovered differences in subunit-specific AMPAR trafficking events between hippocampal and cortical neurons that we propose play a role in the differential vulnerabilities to ischaemia between these neuronal types observed in vivo (Blanco-Suarez et al., 2014, J. Biol. Chem; Koszegi et al., 2017, Scientific Reports).