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:
1) 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).
2) 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.