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.
References
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, J.F. and Greger, I.H. (2016)
The dynamic AMPA receptor extracellular region: A platform for synaptic protein interactions.
J Physiol. 594, 5449-58. -Review-
Greger, I.H. et al. (2017)
Structural and functional architecture of AMPA-type glutamate receptors and their auxiliary proteins.
Neuron 94, 713-30. -Review-
Greger IH, Mayer ML. (2019)
Structural biology of glutamate receptor ion channels:towards an understanding of mechanism.
Curr Opin Struct Biol. 57,185-195. -Review-
Herguedas, B., García-Nafría, J., Cais, O., Fernández-Leiro, R., Krieger, J., Ho, H. and Greger. I.H. (2016)
Structure and organization of heteromeric AMPA-type glutamate receptors.
Science 352:aad3873.
Herguedas B, Watson JF, Ho H, Cais O, García-Nafría J, Greger IH. (2019)
Architecture of the heteromeric GluA1/2 AMPAreceptor in complex with the auxiliary subunit TARP γ8.
Science 364:eaav9011.
Herguedas B, Kohegyi BK, Dohrke JN, Watson JF, Zhang D, Ho H, Shaikh SA, Lape R, Krieger JM, Greger IH. (2022).
Mechanisms underlying TARP modulation of the GluA1/2-γ8 AMPA receptor.
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Watson FF, Ho H, and Greger IH . (2017)
Synaptic transmission and plasticity require AMPA receptor anchoring via its N-terminal domain.
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Watson et al., (2021)
AMPA receptor anchoring at CA1 synapses is determined by an interplay N-terminal domain and TARP γ8 interaction.
Nat Commun. 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. (2022)
Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics.
www.biorxiv.org/content/10.1101/2022.09.25.509219v1
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 10.1038/s41586-023-06528-0.