AMPA receptor diversity and dynamics during excitatory synaptic transmission

Neuronal communication occurs primarily through chemical synapses, specialised into a pre and postsynaptic side. By employing AMPA receptors (AMPARs), the postsynaptic cell can respond to presynaptic glutamate release with millisecond-timescale precision. The diversity of AMPAR subtypes across the brain is vast, with each subtype providing unique signalling properties. The composition and organisation of AMPARs therefore determines the fidelity of excitatory synaptic transmission and enables synaptic plasticity. Distinct functional properties are conferred on the AMPAR tetramer by the choice of core subunit (GluA1-4), as well as their association with various auxiliary subunits. Using results from a combination of electrophysiology and light microscopy, this thesis probes the synaptic trafficking and short-term and long-term plasticity behaviour of GluA1-4. The sequence diverse N-terminal domains (NTD) each possess subunit-specific structural features, which are here shown to affect the synaptic function of the receptor. The NTD of GluA2 forms a stable tetrameric interface, enabling efficient synaptic anchoring. This can be disrupted by both F231A mutation and H208 protonation, increasing receptor mobility and depressing short-term plasticity responses. Likewise, GluA4 forms a similar NTD interface, the disruption of which prevents GluA4 from potentiating synaptic transmission. GluA3 instead forms unique NTD interfaces, which influence surface trafficking and selective heteromerisation of the receptor. Whereas, GluA1 displays a mobile NTD tier and therefore uses different mechanisms involving the C-terminal domain to be recruited to the synapse. This thesis works towards gaining a basic understanding of firstly the function each AMPAR subtype, and secondly the mechanisms selectively employing each subtype, which would open the possibility of therapeutic regulation of AMPARs in disease states.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2025

Author dc:creator

• Stockwell, Imogen

Advisor dc:contributor.advisor

• Greger, Ingo

• glutamate receptor
• synaptic transmission
• synaptic plasticity
• AMPA receptor

Licence

• https://www.repository.cam.ac.uk/bitstreams/73988627-3f32-4d4f-80f3-e9eefab5e1af/download
• http://purl.org/NET/rdflicense/allrightsreserved

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.126208

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/396984