My PhD thesis: Investigating chloride dynamics in physiological processing and epilepsy using computational methods
Christopher B. Currin
University of Cape Town
In fulfilment of the requirements for the degree
Doctor of Philosophy in Neuroscience
Supervised by Dr Joseph Raimondo
Abstract
A fundamental unit of computation in the brain is the neuron, whose output reflects neurological information processing. A critical determinant of neuronal output and the stability of neuronal networks is the modulation of activity by inhibitory synaptic inputs. Underlying fast synaptic inhibition is chloride-permeable GABAA receptors. Consequently, the transmembrane chloride gradient influences the functional properties of inhibitory synapses. How changes in chloride concentration alter the output of single neurons and the stability of brain networks is incompletely understood. In this thesis, I developed computational models of single neurons, neuronal dendrites, and networks of neurons to investigate the role of chloride dynamics in neurological processing and unrelenting epileptic seizure activity.
In multi-compartment neurons, I found that synaptic input can lead to subcellular variations in chloride concentration, which had a significant effect on the ability of dendritically targeted inhibition to offset neuronal input-output curves over time. Importantly, the observed effects of experimentally parametrised chloride dynamics on the neuronal output function were entirely mediated by changes to the GABAA receptor reversal potential.
In dendrites, I discovered that dynamic chloride decreased the local inhibitory effect of GABAA synapses on dendritic excitability but maintained the ability of multiple synapses to accumulate their inhibitory effectiveness at dendritic junctions. The effect depended non-linearly on synaptic location, reversal potential, and distribution. Additionally, I characterised how GABAA receptors make spatial trade-offs in dendrites between maximising their inhibitory effect at a junction and their susceptibility to progressive degeneration due to chloride accumulation.
Finally, I established a spiking neural network model of status epilepticus (unrelenting seizure activity) by recapitulating multiple experimental findings. The model’s mechanisms revealed dynamical behaviour dependent on the inhibitory population and its connections to the excitatory population. By accounting for dynamic chloride, I determined the required strength of chloride extrusion to recover the network to normal given certain pathological levels of intracellular chloride. These findings have clinical relevance for the management of patients with status epilepticus.
Together, the work in my thesis enhances our understanding of the relevance of chloride ion dynamics for both basic neuronal functioning and the management of unrelenting seizure activity.
Acknowledgements
- To my supervisor, Joe Raimondo, you are my hero. Through your passion for neuroscience and pushing the boundaries of what I thought possible for South African neuroscience, you have made me want to be a better scientist. Through your compassion for people and caring about your students’ wellbeing, you have made me want to be a better person. Your scientific mentorship and support for my personal development are an inspiration for me to do more for others. I wish every student could have a supervisor as amazing as you. I hope I can make you proud. I appreciate you.
- To Tim Vogels, thank you for being a gracious host at Oxford, for strongly pushing computational neuroscience in Africa, and for believing in my future. I trust you.
- To Andrew Trevelyan and Henning Sprekeler, thank you for guiding me on my scientific journey by providing valuable input into this work. I admire you.
- To the Raimondo Lab, thank you for making going to the lab worthwhile when I could be working at home instead. Your diverse backgrounds are a window into the best of science. Always changing but consistently excellent, I support you.
- To my dear friends, thank you for sticking by me as we have grown over the years. I enjoy you.
- To my editorial team of Chad Beyer, Kira Düsterwald, and Bill Podlaski, thank you for believing in my journey and for supporting me in your unique ways. Your critical, thoughtful feedback with kind words is always welcome. I recognise you.
- To the men in my family, Dad, Mike, and Neil, for acting impressed by what I say even if you do not know what it means. Your unconditional support has made this journey possible. I rely on you.
- To my Mom, for being my biggest champion. You have provided unparalleled support and understanding. Your influence has moulded me into the person I am today and will always guide me. I love you.
- And finally to Pam, for always asking “are you sure?” about my science. For always believing in me, sharing your zest for life, and for so much more. Your love and support are everything to me. I am you.