Information transfer and storage in the nervous system occurs at synapses. Ionotropic glutamate receptors mediate the majority of excitatory signal transmission; AMPA-type glutamate-receptors (AMPARs) also centrally contribute to synaptic plasticity, a process that underlies learning. 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 mechanisms underlying AMPA-R regulation and signalling 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. This will include:

1. A combination of superresolution microscopy and 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 to and clustering at synapses.
2. Using cryo-EM (electron-cryo microscopy), we will sample the functional relevance of the AMPAR conformational spectrum (Herguedas et al., 2016), and how this is influenced by various AMPAR auxiliary proteins to ultimately tune synaptic transmission and plasticity (Greger et al.,2017) (in collaboration with Dr. Radu Aricescu).

References

Greger, I.H. 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. and Greger. I.H. (2016)
Structure and organization of heteromeric AMPA-type glutamate receptors.
Science 352:aad3873.

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. doi: 10.1113/JP271844.

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.