Structure and signalling of AMPA glutamate receptors in synaptic plasticity

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) ion channels, are the main mediators of signal transmission, and centrally contribute to synaptic plasticity. Malfunction of these receptors underlies various neurological disorders such as epilepsy, pain and neurodegeneration. 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 super-resolution 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 CA1 hippocampal 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 (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:

1) Using a combination of electrophysiology, cell biology and imaging of synaptic AMPA-Rs in brain slices, we will study synaptic plasticity mechanisms. We will ask how AMPA-R auxiliary subunits and synaptic cleft proteins impact receptor recruitment to synapses and their signalling properties at synapses (Greger et al., 2017; Watson et al., 2017; Watson et al., 2020). We will also assay the impact of novel AMPA-R therapeutics on AMPA-R mediated synaptic plasticity (Zhang et al. 2023a).

2) Using cryo-EM (electron-cryo microscopy), we will determine both the structure of recombinant AMPA-R complexes (Herguedas et al., 2016; Herguedas et al., 2019; 2022; Greger & Mayer 2019; Zhang et al., 2021; Zhang et al., 2023b; Ivica et al., 2024) and of native synaptic receptors, isolated from brain. 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.