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Role of glutamate receptor dynamics in synaptic plasticity

  • Full or part time
  • Application Deadline
    Tuesday, December 03, 2019
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description


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. My lab is utilizing various approaches, including structural biology, cell biology, electrophysiology and super-resolution imaging to understand the mechanisms that underlie AMPA-R regulation and signalling at synapses. 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 regulation of synaptic AMPA-Rs via the large receptor N-terminal domain (NTD) (Herguedas al., 2016; Watson et al., 2017) to ultimately understand how AMPAR are slotted into synapses during learning (Buonarati et al., 2019). This will include:

1) A combination of superresolution microscopy and brain slice electrophysiology to study how the NTD, via interactions with synaptic proteins (Garcia-Nafria et al., 2016) including AMPA-R auxiliary subunits (Cais et al., 2014), impacts AMPAR recruitment and clustering at synapses (Watson et al., 2017).

2) Using cryo-EM (electron-cryo microscopy), we determine the structure of synaptic AMPAR complexes (Herguedas et al., 2019), sample the AMPAR conformational spectrum (Herguedas et al., 2016) and study how this is influenced by various AMPAR auxiliary proteins (Greger et al.,2017; Greger & Mayer 2019).

Funding Notes

Please see the LMB PhD website for further details: View Website

References


Greger IH, Mayer ML. (2019)
Structural biology of glutamate receptor ion channels:towards an understanding of mechanism. Curr Opin Struct Biol. 57,185-195.

Herguedas B, Watson JF, Ho H, Cais O, García-Nafría J, Greger IH. (2019) Architecture of the heteromeric GluA1/2 AMPA receptor in complex with the auxiliary subunit TARP γ8. Science 364:eaav9011.

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.

Greger IH et al., (2017) Structural and functional architecture of AMPA-type glutamate receptors and their auxiliary proteins. Neuron 94, 713-30.

Watson et al., (2017) Synaptic transmission and plasticity require AMPA receptor anchoring via its N-terminal domain. eLife e23024.

Herguedas B, García-Nafría J, Cais O, Fernández-Leiro R, Krieger J, Ho H, Greger IH. (2016) Structure and organization of heteromeric AMPA-type glutamate receptors. Science 352:aad3873.

García-Nafría J, Herguedas B, Watson JF, Greger IH. (2016) The dynamic AMPA receptor extracellular region: A platform for synaptic protein interactions. J Physiol. 594, 5449-58.

Cais O et al. (2014) Mapping the interaction sites between AMPA receptors and TARPs reveals a role for the receptor N-terminal domain in channel gating. Cell Reports, 9, 728-40.



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