Information transfer in the brain occurs at synapses, where memories are stored as a result of synaptic plasticity processes. AMPA-type glutamate-receptors (AMPARs), the main mediators of signal transmission, centrally contribute to synaptic plasticity. Malfunction of these receptors underlies various neurological disorders such as epilepsy 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 poorly understood mechanisms (Greger et al., 2017). We are utilizing various approaches, including structural biology, cell biology, and electrophysiology to understand the mechanisms that underlie AMPA-R regulation and signalling. Our ultimate goal is to decipher the molecular mechanisms underlying information storage at synapses.
We will be capitalising on our structural and functional data to explore the regulation of AMPA-R/auxiliary subunit complexes prevailing at defined synapses (Herguedas al., 2019; Zhang et al., 2021), with the ultimate aim to understand how AMPAR are slotted into synapses during learning (Buonarati et al., 2019; Garcia-Nafria et al., 2016; Watson et al., 2017; Watson et al., 2021).
Ph.D projects are available for either of the following 2 topics:
- Using electrophysiology of recombinant AMPA-Rs (expressed in HEK cells) and of synaptic AMPARs in brain slices combined with cell biology, we will ask how AMPA-R auxiliary subunits impact signalling and receptor recruitment to synapses (Greger et al., 2017; Watson et al., 2017; Watson et al., 2020). We will also assay the impact of novel AMPAR therapeutics on AMPA-R signal transmission.
- Using cryo-EM (electron-cryo microscopy), we will determine the structure of recombinant ANPA-R complexes resembling synaptic receptors (Herguedas et al., 2016; Herguedas et al., 2019; Greger & Mayer 2019; Zhang et al., 2021). We will also investigate AMPA-R auxiliary subunit complexes associated with small-molecule therapeutics and with modulatory lipids.
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, 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., 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.
Watson FF, Ho H, and Greger IH . (2017)
Synaptic transmission and plasticity require AMPA receptor anchoring via its N-terminal domain.
eLife e23024.
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.
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.