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Firing Dynamics of Thalamic Neurones During Genetically Determined Experimental Absence Seizures

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Firing Dynamics of Thalamic Neurones During Genetically Determined Experimental Absence Seizures Firing Dynamics of Thalamic Neurones During Genetically Determined Experimental Absence Seizures A thesis submitted to Cardiff University for the degree of Doctor of Philosophy by Cian McCafferty BSc (Hons) School of Biosciences, Cardiff University, February 2014 Declaration and Statements No portion of this thesis has been submitted in substance for any other degree or award at this or any other university or place of learning, nor is being submitted concurrently in candidature for any degree or other award. Signed ………………………………………………………. (candidate) Cian McCafferty This thesis is the result of my own work except where otherwise indicated by specific reference, and any views expressed are my own. Signed ………………………………………………………. (candidate) Cian McCafferty I hereby give permission for my thesis, if accepted, to be made available for photocopying and for inter-library loan, and for the title and summary to be made available to outside organisations. Signed ………………………………………………………. (candidate) Cian McCafferty 2 Summary Absence seizures (ASs) are the predominant form of seizure featuring in the idiopathic generalised epilepsies, and are the only seizure type of childhood absence epilepsy. They are characterised by behavioural arrest, impairment of consciousness and an electrographic signature of spike-and-wave discharges (SWDs) and are associated with psychosocial and cognitive impairment of development. The seizures are known to arise in the thalamocortical network, but the firing dynamics of thalamic neurones during seizure is not known. In vivo and in vitro studies have yielded contradictory results, suggesting predominant silence and regular burst firing respectively, but no studies have previously recorded from intact, single thalamic neurones in a freely moving model of absence epilepsy. In this thesis it has been shown that, in Genetic Absence Epilepsy Rats from Strasbourg, thalamocortical (TC) neurones are mostly either silent or fire single spikes irregularly but synchronously during AS. T-type calcium channel-mediated bursts in neurones of the reticular thalamic nucleus (nRT) were frequently observed during full seizure expression. These cells expressed varied firing patterns ranging from regular burst firing to predominant silence, with similarly varying degrees of synchrony. It is also suggested that the nRT burst firing observed may be required for seizure generation. T-type calcium channel-mediated burst firing of TC neurones is neither necessary for, nor commonly observed in, the full generation or propagation of absence seizures These results suggest that TC neurones are predominantly silent during AS. This is compatible with the idea of a cortical seizure initiator and driver, as suggested by the cortical initiation site and cortical abnormalities observed in multiple experimental AS models. The observations herein also confirm that the temporal relationship between thalamic firing and SWDs previously observed in anaesthetised animals is maintained in the freely moving condition, but suggest that there is a greater incidence of asynchronous thalamic activity during AS (particularly of nRT neurones) than previously suggested. The firing dynamics of thalamic neurones observed are a crucial step towards understanding TC network activity during AS, and provide a significant insight into the role of the thalamus in alterations of sensation, movement, and consciousness associated with these seizures. 3 Collaborations Animal implantations and data collection in Chapter 3 were performed together with Dr. François David. 4 Acknowledgements I wish to thank the people who have helped me over the course of my PhD. Firstly I would like to thank my supervisor Vincenzo Crunelli, who has always been generous with his time and resources as well as conscientious in his supervision and scientific direction, for the opportunity to undertake this PhD. All the members of the Crunelli lab for their help and advice on scientific issues, particularly Bill for statistics and experimental design, Hannah for surgical practice and treats as I was writing up, and François for TC network dynamics and spike sorting. Marcello and Joscha for being willing to talk about anything and everything with me, and for reviving my interest in scientific enquiry at times when it was flagging – I would have been far less involved in, and less rewarded by my PhD without them. Tim for always being up for a chat, impressing me with his competitive dedication to cycling, and for all his work as our lab manager. Everyone who spent some time working in the lab, particularly Nihan and Brittany, for bringing some perspective of the wider world of neuroscience. My parents, brother Rory, and the rest of my family for their constant support and interest in my somewhat esoteric chosen field of study, as well as their ability to put things in context and take the pressure off me when I needed that. Finally and most importantly I would like to thank Gabster. For not letting me run away when I was writing up, for keeping me going with superhuman levels of positivity and support (and food), for making sure the last four years of my life would have been the best whatever I happened to be doing, and for generally being a better person than I could have ever realistically hoped to meet. 5 Table of Contents FIRING DYNAMICS OF THALAMIC NEURONES DURING GENETICALLY DETERMINED EXPERIMENTAL ABSENCE SEIZURES ..................................................................................... 1 DECLARATION AND STATEMENTS ...................................................................................................... 2 SUMMARY .................................................................................................................................... 3 COLLABORATIONS .......................................................................................................................... 4 ACKNOWLEDGEMENTS ................................................................................................................... 5 Abbreviations ...................................................................................................................... 12 CHAPTER 1 – INTRODUCTION......................................................................................................... 15 1.1 Absence Seizures ..................................................................................................... 15 ....................................................................................................................................................................... 16 Figure 1.1 Initiation sites in AS –fMRI evidence ..................................................................................... 16 1.1.1 Childhood Absence Epilepsy (CAE).................................................................................................. 17 1.1.1.1 Clinical Features .................................................................................................................... 17 Table 1.1 Generalised seizures ............................................................................................................. 18 1.1.1.2 EEG Features ......................................................................................................................... 19 Figure 1.2 Appearance of a SWD............................................................................................................ 20 1.1.1.3 Epidemiology & Aetiology ..................................................................................................... 21 1.1.1.4 Treatment ............................................................................................................................. 23 1.1.1.5 Prognosis ............................................................................................................................... 24 1.1.2 Summary of human absence seizures ............................................................................................. 24 1.2 Functional Anatomy of the Thalamocortical System .............................................. 25 1.2.1 Overview of the network ................................................................................................................ 25 1.2.2 Thalamus ......................................................................................................................................... 26 1.2.2.1 Ventrobasal nucleus of the thalamus .................................................................................... 28 1.2.2.2 Reticular thalamic nucleus .................................................................................................... 29 1.2.3 Somatosensory cortex .................................................................................................................... 29 1.2.4 Thalamic neurone connectivity ....................................................................................................... 30 1.2.4.1 Anatomical connections of thalamic neurones ..................................................................... 30 Figure 1.4 Thalamocortical network connectivity – schematic representation ..................................... 32 1.2.4.2 Synaptic properties of thalamic neurones ............................................................................ 34 1.2.5 Intrinsic membrane currents of thalamocortical network neurones .............................................. 35 1.2.5.1 Na+ currents .........................................................................................................................
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