About the Project
Excitatory synapses are the principal sites at which information is integrated and stored in the brain, yet we still lack a molecularly resolved understanding of how their strength and plasticity are determined. AMPA glutamate receptors (AMPA-Rs) sit at the centre of this process, converting glutamate release into excitatory signals. AMPA-Rs are highly diverse signaling complexes. Their properties are shaped by combinations of pore-forming subunits and auxiliary proteins, whose composition…
varies between cell types, synapses and brain regions (Greger et al., 2017). This molecular diversity represents a fundamental, but largely unexplored, layer of synaptic computations.
Our lab aims to decode AMPAR signalling complexity from atomic structure to neural circuits, establishing how receptor composition determines excitatory transmission, plasticity, and ultimately network computations. 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 at functionally diverse hippocampal synapses (Zhang et al., 2021; Herguedas et al., 2022; Zhang et al., 2023; Pokharna et al., 2025), 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; 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 patch-clamp electrophysiology, multi-electrode arrays and super-resolution imaging in brain tissue, we will study AMPA-R distribution across synapses at the nano-scale and their 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., 2021; Fuchsberger et al., 2025).
- Using cryo-EM (electron-cryo microscopy), we will determine the structure of recombinant AMPA-R complexes (Herguedas et al., 2022; Zhang et al., 2021; Zhang et al., 2023b; Ivica et al., 2024; Pokharna et al., 2025) and architectures of native synaptic receptors, isolated from different brain regions (Scrutton et al., 2026, Han et al., 2026).
We also seek to develop small-molecule therapeutics targeting AMPA-R auxiliary subunit complexes, using cryo-EM to define their structures (Zhang et al. 2023a), and electrophysiology to assess their impact on AMPA-R mediated synaptic plasticity.
References
Greger IH et al., (2017) Structural and functional architecture of AMPA-type glutamate receptors and their auxiliary proteins. Neuron 94, 713-30. –Review-
Han, Y. et al. Structural basis for GluA1 AMPA receptor regulation by PRRT1/SynDIG4 in LTP. bioRxiv, 2026.2006.2024.734257 (2026).
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-
Scrutton, A. M. et al. Structure and organization of AMPA receptor-TARP complexes in the mammalian cerebellum. Science 391, 1361-1367 (2026).
Stockwell I, Watson JF, Greger IH. (2024) Tuning synaptic strength by regulation of AMPA glutamate receptor localization. Bioessays 46(7):e2400006. – Review -
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.
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