Curtis, Ashton;
(2024)
Building Stronger Synapses:
Investigating the Structural Role of
CaMKII in Long-Term Potentiation.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The process of learning and memory storage relies on long-lasting changes in the strength of synaptic connections. In excitatory synapses, long-term potentiation (LTP) is triggered by high Ca2+ influx through NMDA-type glutamate receptors (NMDARs). Activation of NMDARs leads to the stimulation of the abundant Ca2+/CaM-dependent protein kinase II (CaMKII), which phosphorylates key proteins to increase postsynaptic responsiveness. In addition to its role in phosphorylating proteins, CaMKII also plays a structural role by supporting enlarged synapses through its ability to nucleate multivalent interactions with other proteins. In this study, I investigate the structural role of CaMKII with a focus on understanding how it mediates interactions that regulate spine morphology at a molecular level. I reveal that association of CaMKII with the actin cross-linking protein α-actinin-2 is elevated following NMDAR activation that induces LTP. Furthermore, I find that this interaction is necessary for the formation of structure of enlarged dendritic spines. CaMKII-α-actinin-2 association occurs within 2 minutes of NMDAR activation, persists for hours, and is not influenced by CaMKII autophosphorylation. I also examine a widely utilised phospho-deficient CaMKII mutant (T305A/T306A) and show that it has a gain-of-function ability to bind α-actinin-2 tightly, which has important implications for interpretations of earlier studies involving this CaMKII variant. Together, my research findings further our understanding of the role of CaMKII in LTP, revealing a new layer of sophistication to its function.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Building Stronger Synapses: Investigating the Structural Role of CaMKII in Long-Term Potentiation |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10186298 |
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