Mechanisms and machinery mediating AMPA receptor anchoring in synaptic plasticity
Award Number
BB/T015993/1Status / Stage
CompletedDates
1 July 2020 -30 June 2023
Duration (calculated)
02 years 11 monthsFunder(s)
BBSRC (UKRI)Funding Amount
£431,935.00Funder/Grant study page
BBSRC UKRIContracted Centre
MRC Laboratory of Molecular BiologyPrincipal Investigator
Dr Ingo GregerPI Contact
ig@mrc-lmb.cam.ac.ukWHO Catergories
Understanding Underlying DiseaseDisease Type
Dementia (Unspecified)CPEC Review Info
| Reference ID | 683 |
|---|---|
| Researcher | Reside Team |
| Published | 07/07/2023 |
Data
| Award Number | BB/T015993/1 |
|---|---|
| Status / Stage | Completed |
| Start Date | 20200701 |
| End Date | 20230630 |
| Duration (calculated) | 02 years 11 months |
| Funder/Grant study page | BBSRC UKRI |
| Contracted Centre | MRC Laboratory of Molecular Biology |
| Funding Amount | £431,935.00 |
Abstract
The plastic nature of a synapse, where the flow of information is able to induce rapid and long-lasting changes in synaptic strength, is central to our understanding of learning and memory. The AMPA-type glutamate receptor (AMPAR), is key to this process. Postsynaptically localised AMPARs are activated by presynaptically released glutamate, depolarising the postsynaptic cell to achieve synaptic transmission. By modulating the extent of AMPAR activation, the strength of transmission can be tuned. Therefore, elucidating the mechanisms controlling the trafficking and localisation of synaptic AMPARs is essential to understanding memory formation. At hippocampal synapses, the majority of AMPARs consists of GluA1/2 and GluA2/3 heteromers. While the activity-dependent trafficking of GluA1-containing AMPARs to synaptic sites has long been associated with synaptic potentiation, the precise roles and regulation of these different receptors in synaptic transmission and plasticity remain unclear. In this project, we propose to use cutting-edge technology to visualise the dynamics of AMPAR function in synaptic plasticity, in intact neuronal circuits in the most refined manner to date. CRISPR/Cas9 genome editing coupled with 3D STORM imaging in brain tissue will allow visualisation of the localisation of endogenous AMPAR heteromers within the synapse on the nanoscale. Building on our recent insights into the mechanisms controlling AMPAR synaptic anchoring, we will characterise how interactions control receptor localisation at synaptic sites and aim to identify proteins that mediate anchoring (using a bioID proximity labeling). We aim to resolve the synaptic receptor rearrangements occurring at baseline conditions and in response to synaptic plasticity. Together, this study aims to reveal the nanoscale rearrangements and mechanisms of synaptic AMPARs during plasticity, which tune synaptic transmission and facilitate information storage in the brain.
Aims
Building on our recent insights into the mechanisms controlling AMPAR synaptic anchoring, we will characterise how interactions control receptor localisation at synaptic sites and aim to identify proteins that mediate anchoring (using a bioID proximity labeling). We aim to resolve the synaptic receptor rearrangements occurring at baseline conditions and in response to synaptic plasticity. Together, this study aims to reveal the nanoscale rearrangements and mechanisms of synaptic AMPARs during plasticity, which tune synaptic transmission and facilitate information storage in the brain.