Information transfer in the brain occurs at synapses, where memories are stored as a result of synaptic plasticity processes. AMPA-type glutamate-receptors (AMPA-Rs), are the main mediators of signal transmission, and centrally contribute to synaptic plasticity. Malfunction of these receptors underlies various neurological disorders. AMPA-R signalling is controlled at multiple levels and includes a variety of associated proteins, that act in a cell-type selective fashion through incompletely understood mechanisms (Greger et al., 2017). We are utilizing various approaches, including structural biology, cell biology, and electrophysiology combined with imaging, to understand the mechanisms that underlie AMPA-R operation. Our ultimate goal is to decipher the molecular mechanisms underlying information storage at synapses. We also seek to develop AMPA-R selective therapeutics, to combat neurological disorders and boost cognition.
We will be capitalising on our structural and electrophysiological data to explore the regulation of AMPA-R/auxiliary subunit complexes prevailing at hippocampal and cerebellar synapses (Herguedas al., 2019; Zhang et al., 2021; Herguedas et al., 2022; Zhang et al., 2023), with the ultimate aim to understand how AMPAR are trafficked into synapses during learning, and how diverse auxiliary subunits regulate this process (Buonarati et al., 2019; Garcia-Nafria et al., 2016; Watson et al., 2017; Watson et al., 2021; Stockwell et al., 2024).
Ph.D projects are available for the following topics:
- Using a combination of electrophysiology, cell biology and imaging of synaptic AMPA-Rs in brain slices, we will study AMPA-R synaptic recruitment during plasticity (LTP). We will ask how AMPA-R auxiliary subunits and synaptic cleft proteins impact receptor trafficking to synapses and their signalling properties at synapses (Greger et al., 2017; Watson et al., 2017; Watson et al., 2020; Fuchsberger et al., 2025). We will also assay the impact of AMPA-R therapeutics on AMPA-R mediated synaptic plasticity (Zhang et al. 2023a).
- Using cryo-EM (electron-cryo microscopy), we will determine both the structure of recombinant AMPA-R complexes (Herguedas et al., 2019; 2022; Zhang et al., 2021; Zhang et al., 2023b; Ivica et al., 2024; Pokharna et al., 2025) and of native synaptic receptors, isolated from different brain regions. We will also investigate AMPA-R auxiliary subunit complexes associated with small-molecule therapeutics and with modulatory lipids (Zhang et al. 2023a), which we seek to develop further.
References relevant to project
Greger IH et al., (2017) Structural and functional architecture of AMPA-type glutamate receptors and their auxiliary proteins. Neuron 94, 713-30.
–Review-
Buonarati OR, Hammes EA, Watson JF, Greger IH, Hell JW. (2019)
Mechanisms of postsynaptic localization of AMPA-type glutamate receptors and their regulation during long-term potentiation.
Sci Signal.12, eaar6889. –Review-
García-Nafría J, Herguedas B, Watson JF, Greger IH. (2016) The dynamic AMPA receptor extracellular region: A platform for synaptic protein interactions. J Physiol. 594, 5449-58. –Review-
Stockwell I, Watson JF, Greger IH. (2024) Tuning synaptic strength by regulation of AMPA glutamate receptor localization.
Bioessays 46(7):e2400006. – Review-
Herguedas B, Watson JF, Ho H, Cais O, García-Nafría J, Greger IH. (2019) Architecture of the heteromeric GluA1/2 AMPA receptor in complex with the auxiliary subunit TARP γ8. Science 364:eaav9011.
Watson JF, Ho H, and Greger IH (2017) Synaptic transmission and plasticity require AMPA receptor anchoring via its N-terminal domain. eLife e23024.
Watson JF, Pinggera A, Ho H, and Greger IH (2021) AMPA receptor anchoring at CA1 synapses is determined by an interplay N-terminal domain and TARP γ8 interaction. Nature Comms. 12, 5083.
Zhang D, Watson JF, Matthews P, Cais O, Greger IH. (2021) Gating and modulation of a hetero-octameric AMPA glutamate receptor. Nature 594, 454-458.
Zhang D, Lape R, Shaikh S, Kohegyi B, Watson JF, Cais O, Nakagawa T, Greger IH. (2023a) Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics. Nat. Commun. 14,1659.
Zhang D, Ivica J, Krieger JM, Ho H, Yamashita K, Stockwell I, Baradaran R, Cais O, Greger IH. (2023b) Structural mobility tunes signalling of the GluA1 AMPA glutamate receptor. Nature 621, 877.
Ivica J, Kejzar N, Ho H, Stockwell I, Kuchtiak V, Scrutton AM, Nakagawa T, Greger IH. (2024) Proton-triggered rearrangement of the AMPA receptor N-terminal domains impacts receptor kinetics and synaptic localization. Nat Struct Mol Biol. 31, 1601.
Fuchsberger T, Stockwell I, Woods M, Brzosko Z, Greger IH, Paulsen O. (2025) Dopamine increases protein synthesis in hippocampal neurons enabling dopamine-dependent LTP.
Elife 13:RP100822. doi: 10.7554/eLife.100822.
Pokharna A, Stockwell I, Ivica J, Singh B, Schwab J, Vega-Gutiérrez C, Herguedas B, Cais O, Krieger JM, Greger IH. (2025) Architecture, dynamics and biogenesis of GluA3 AMPA glutamate receptors.
Nature; doi: 10.1038/s41586-025-09325-z.