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Current projects

Structure and biophysics of major AMPA receptor complexes

AMPAR activation by glutamate involves a spectrum of conformational transitions referred to as ‘gating’. These ultimately open the channel’s gate to permit cation flux and membrane depolarisation. Using a combination of electron cryomicroscopy (cryo-EM), patch-clamp electrophysiology, molecular dynamics simulations, and mass-spectrometry, we study:

  1. the organisation and stoichiometry of predominant AMPAR-auxiliary subunit complexes
  2. how auxiliary subunits influence transitions in the AMPAR gating cycle
  3. the identity, binding sites and role of AMPAR-associated annular lipids
  4. the development of therapeutic ligands targeting predominant AMPAR complexes (in collaboration with AstraZeneca and LifeArc).
cryo-EM structure of an octameric AMPAR complex: GluA1 (blue), GluA2 (red), Tarp gamma8 (green), CNIH2 (yellow)
Response of GluA1 or GluA1+TARP gamma8 to a brief pulse of glutamate

Regulation of AMPA receptor organisation at potentiated synapses

A hallmark of learning (i.e. the encoding and storage of information) is the growth and potentiation of synapses. This process requires the recruitment of AMPARs into the post-synaptic density (PSD) and their accumulation into receptor nano-clusters. A central question is the nature of the machinery facilitating AMPAR organisation at potentiated synapses. To address this we:

  1. investigate essential AMPAR clustering components, through recordings of neurons expressing modified AMPAR complexes (expressed virally in genetically modified mice) 
  2. image the sub-synaptic distribution of AMPAR varieties using 3D STORM and STED, prior to and after synapse potentiation (induced electrically or via 2-photon glutamate uncaging)
  3. identify AMPAR synaptic clustering/anchoring proteins using proximity labelling approaches
  4. re-constitute core clustering elements (identified through the above approaches) together with AMPARs in synthetic ‘hemi-synapses’
Alignment of pre-synapse (pink stain, Basoon) and post-synapse (PSD-95, green). Confocal (left) versus 3D STORM (right). Scale bar = 100 nm.
Simulated synaptic AMPAR responses

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© 2025 · Greger Lab at the MRC Laboratory of Molecular Biology
Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. 01223 267000
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