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Stuart Cull-Candy

Department of Neuroscience, Physiology & Pharmacology

Ca2+-permeable AMPARs and synaptic plasticity

Our experiments, on thin-slices of brain tissue, involve studying synaptic transmission and use of high resolution patch-clamp recording of single-channel currents (NMDAR- AMPAR and GABA receptors) in visually identified neurons. Because we use intact tissue, information is available about the receptor subunits present contributing to the native receptor-channels present in these cells. Our experiments also involve studying genetically modified mice and use of recombinant mutated receptors (composed of known subunits) to provide information about the glutamate receptor-subunits and associated molecules involved in various forms of plasticity and developmental changes. Using these approaches, we have recently been focusing on discovering basic mechanisms that drive the switch in synaptic Ca2+-permeability of AMPARs (see References below).


Until recently, our view of synaptic plasticity was based largely on studies of synapses that express mainly Ca2+- impermeable AMPARs. The Ca2+-permeability of GluR2-lacking AMPARs clearly makes them attractive candidates as mediators of synaptic plasticity — by offering a route for Ca2+ entry independent of NMDARs or voltage-gated Ca2+ channels. Our studies on cerebellar stellate cells have shown that high frequency presynaptic activity induces a type of plasticity in which Ca2+ entry through existing postsynaptic
GluR2-lacking AMPARs triggers a lasting switch in their subunit composition and Ca2+ permeability. The rapid replacement of Ca2+-permeable receptors, by ones containing GluR2, results in a reduced excitatory postsynaptic current -amplitude at negative membrane potentials, probably because of insertion of receptors with a lower mean single-channel conductance; by contrast, the increased excitatory postsynaptic current at depolarized potentials reflects the presence of receptors that are no longer blocked by endogenous intracellular polyamines. We are currently interested in the protein partners involved in the delivery and anchoring of receptors underlying the activity-dependent plasticity of Ca2+- permeable AMPARs, and in basic mechanisms underlying the switch in AMPAR subtype. We are also interested in whether NMDARs and GABA receptors play a role in this plasticity. 


Cull-Candy, S., Kelly, L. & and Farrant, M.  (2006)
Regulation of Ca2+-permeable AMPA receptors: synaptic plasticity and beyond.
Current Opinion in Neurobiology 16, 288-297

Liu, S.J & Cull-Candy, S.G.  (2005)
Subunit interaction with PICK and GRIP controls Ca2+-permeability of AMPARs at cerebellar synapses.
Nature Neuroscience 8, 768-775

Cathala, L., Holderith, N.B. Nusser, Z., DiGregorio, D and Cull-Candy, S.G.  (2005)
Changes in synaptic structure underlie the developmental speeding of AMPA receptor-mediated EPSCs
Nature Neuroscience 8, 1310-1318


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