Pilch, Kjara Sophia;
(2022)
CaV2.2 Channels in Brain Development and Synaptic Plasticity.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
In the mammalian brain, presynaptic CaV2.2 channels play a pivotal role for synaptic transmission by mediating fast neurotransmitter exocytosis via influx of Ca2+ into the active zone at the presynaptic terminal. The distribution and activity of CaV2.2 channels at different synapses and maturity stages in the brain remains to be elucidated. In this study, I first show high levels of CaV2.2 channels in mouse cortex and hippocampus throughout development, persisting into adulthood. In contrast, CaV2.2 channels in the cerebellum and brain stem decreased as the brain matured. I thereafter assessed CaV2.2 channels during homeostatic synaptic plasticity, a compensatory form of homeostatic control preventing excessive or insufficient neuronal activity during which extensive active zone remodelling has been described. In this work I show that chronic silencing of neuronal activity in mature hippocampal cultures resulted in elevated presynaptic Ca2+ transients, mediated by a 30 % increase in CaV2.2 channel levels at the presynapse. Next, this work focussed on α2δ-1 subunits, important regulators of synaptic transmission and CaV2.2 channel abundance at the presynaptic membrane. Here, I show that α2δ-1- overexpression reduces the contribution of CaV2.2 channels to total Ca2+ flux without altering the amplitude of the Ca2+ transients. Finally, levels of endogenous α2δ-1 decreased during homeostatic synaptic plasticity, whereas the overexpression of α2δ-1 prevented homeostatic synaptic plasticity in hippocampal neurons. Together, this study reveals a key role for CaV2.2 channels and novel roles for α2δ-1 during plastic synaptic adaptation.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | CaV2.2 Channels in Brain Development and Synaptic Plasticity |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. 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 > 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 UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10155462 |
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