Jones, Steffan Pettengell;
(2022)
Assessing Homeostatic Plasticity in Genetic and Acquired Epilepsies.
Doctoral thesis (Ph.D), UCL (University College London).
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Assessing Homeostatic Plasticity in Genetic and Acquired Epilepsies - Steffan Jones (SN - 13019928).pdf - Accepted Version Download (10MB) | Preview |
Abstract
Homeostatic plasticity allows the brain to correct deviations from physiological levels of activity to maintain long term stability. Despite this remarkable level of control, epilepsy is a disease characterized by both cellular and circuit hyperexcitability that homeostatic plasticity seemingly fails to suppress. In this thesis, I demonstrate that during both acquired and genetic epileptogenesis, neurons display numerous changes consistent with homeostatic responses to nascent hyperactivity and that early stages of genetic epileptogenesis are characterized by increased levels of homeostatic response. In Dravet syndrome, a severe genetic epilepsy of infancy, loss-of-function mutations to the voltage-gated sodium channel NaV1.1 are found in the majority of patients. These mutations generate network hyperactivity due to loss of inhibitory interneuron excitability. Using a mouse model of Dravet, I demonstrate that the first cells to display altered intrinsic properties may in fact be excitatory pyramidal cells. I demonstrate that both diminished intrinsic excitability and increased responsiveness to altered activity levels are seen in pyramidal cells at early stages of Dravet. I then show that the later onset of inhibitory hypofunction generates synaptic excitation/inhibition imbalance and hyperactivity. This hyperactivity appears to drive diminished intrinsic excitability and synaptic downscaling in pyramidal cells, amongst other changes consistent with homeostatic plasticity. I also demonstrate the viability of a future approach to better assess homeostatic responses to models of acquired epileptogenesis. This approach can contribute to answering the much debated questions about both the pathophysiology of acquired epilepsy and the much understudied mechanisms of homeostatic responses to hyperactivity.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Assessing Homeostatic Plasticity in Genetic and Acquired Epilepsies |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2021. 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. |
| Keywords: | Epilepsy, Homeostatic plasticity, Electrophysiology, Dravet syndrome |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10147136 |
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