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Hippocampal Neurophysiology During Exploratory Behaviour and Sleep in Rats Heterozygous for the Psychiatric Risk Gene Cacna1c

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Hippocampal Neurophysiology During Exploratory Behaviour and Sleep in Rats Heterozygous for the Psychiatric Risk Gene Cacna1c Hippocampal Neurophysiology During Exploratory Behaviour and Sleep in Rats Heterozygous for the Psychiatric Risk Gene Cacna1c Edward Richard Morrell A Thesis Presented for the Degree of Doctor of Philosophy December 2020 Word Count: 43,582 Abstract Genome-wide association studies reveal that calcium channel gene variants confer risk for psychiatric disorders across diagnostic categories. One consistently implicated gene is CACNA1C, a gene encoding the α1 pore-forming subunit of the L-type calcium channel. Recent rodent research highlights an important role for Cacna1c in hippocampal synaptic plasticity and related cognition, yet little is known about the effects of reduced Cacna1c gene dosage on hippocampal neurophysiology in vivo. Using tetrodes targeted to the dorsal CA1 I recorded single unit and local field potential activity in rats heterozygous for Cacna1c during free exploration and rest. Cacna1c heterozygous rats displayed enlarged place-fields and an associated reduction in place-cell spatial information content during runs on a linear track in a familiar and novel orientation, while place-cell activity during exploration of a novel open-field was intact. In addition, while 6-10Hz theta and 25-140Hz gamma rhythms were comparable in frequency and power in heterozygotes, their dependence on locomotion was compromised. Phase- amplitude coupling between theta and slow-gamma was also attenuated in Cacna1c heterozygous rats running on the track in a novel orientation. Hippocampal recordings at rest revealed intact 120-250Hz sharp-wave ripple oscillations, yet an enhanced participation of individual neurons in sharp-wave ripple events in Cacna1c heterozygotes. Despite the elevation in ripple-associated activity, coactivity between cell pairs during sharp-wave ripple events was markedly impaired. Changes to neurophysiology during sleep-associated oscillations appeared independent of global sleep architecture, since Cacna1c heterozygotes showed normal circadian activity patterns. Finally, combining genetic L-type calcium channel hypofunction with NMDA receptor blockade using systemic ketamine administration, did not exacerbate hippocampal deficits in Cacna1c heterozygotes, indicating a divergence of these biological pathways. This research reveals an important role for CACNA1C in hippocampal neurophysiology that may contribute to cognitive deficits associated with psychiatric risk. iii iv Acknowledgements I would like to thank my supervisors Professor Matt Jones, Professor Lawrence Wilkinson and Professor Jeremy Hall for giving me the opportunity to undertake this research project and for their ongoing support, advice and inspiration over the last four years. Without their hard work and encouragement this would not have been possible. I would also like to thank all members of the Jones Lab, both past and present, for their continuous technical support and assistance, intellectual stimulation, feedback and scrutiny of my research, and friendship throughout the course of my PhD. In particular: Dr Aleks Domanski, Dr Ullrich Bartsch, Dr Alice Fodder, Dr Julia Heckenast, Dr Emma Roscow, Dr Tim Howe, Dr Ross Purple, Dr Pratap Tomar, Dr Silviu Rusu, Amber Roguski, Dr Eszter Kormann, Daniel Titheradge and Luke Burguete. I would like to thank Dr Cezar Tigaret and the rest of my collaborators in Cardiff for their insightful research that provided much of the basis for the work presented in this thesis. Finally I would like to thank my parents and family for their support over the past four years and for providing me with a place to live and write my thesis amidst the coronavirus pandemic. This work was funded jointly by the Wellcome Trust strategic award DEFINE, Cardiff University School of Psychology and School of Medicine, and supported by an MRC Senior Non-clinical Research Fellowship awarded to Professor Matt Jones. v vi Table of Contents Contents Chapter 1 Introduction ....................................................................................................... 1 1.1. Introduction ............................................................................................................. 1 1.1.1. Heritability of Psychiatric Illness ....................................................................... 1 1.1.2. Shifting Sands of Psychiatric Research............................................................ 5 1.1.3. Animal Models of Psychiatric Disease ............................................................. 6 1.2. CACNA1C .............................................................................................................. 7 1.2.1. CACNA1C Genetic Variation ........................................................................... 7 1.2.2. CACNA1C Genetic Animal Models .................................................................. 8 1.2.3. L-Type Calcium Channel Properties ................................................................ 9 1.2.4. L-Type Calcium Channels & Synaptic Plasticity ............................................. 11 1.2.5. Behavioural Effects of CACNA1C Gene Variation .......................................... 14 1.2.6. Effects of CACNA1C Gene Variants on Brain Activity .................................... 15 1.3. The Hippocampus ................................................................................................. 16 1.3.1. The Roles of the Hippocampus ...................................................................... 16 1.3.2. The Hippocampus in Psychiatric Disease ...................................................... 17 1.3.3. Hippocampal Electrophysiology ..................................................................... 18 1.4. Thesis Aims .......................................................................................................... 26 Chapter 2 General Methods ............................................................................................. 27 2.1. Animals ................................................................................................................. 27 2.2. In Vivo Electrophysiology ...................................................................................... 27 2.2.1. Tetrode Design & Construction ...................................................................... 27 2.2.2. Surgical Procedure ........................................................................................ 29 2.2.3. Data Acquisition System ................................................................................ 30 2.2.4. Tetrode Targeting .......................................................................................... 31 2.3. Habituation & Behaviour ....................................................................................... 31 2.3.1. Recording Room Setup .................................................................................. 32 2.3.2. Habituation .................................................................................................... 32 2.4. Verification of Electrode Position ........................................................................... 32 2.4.1. Lesioning & Perfusion .................................................................................... 32 2.4.2. Histology ........................................................................................................ 32 2.5. Data Analysis ........................................................................................................ 33 2.5.1. Spike Sorting ................................................................................................. 33 2.5.2. Statistics ........................................................................................................ 33 vii Table of Contents Chapter 3 Place-Cell & Network Physiology During Free Exploration in Cacna1c Heterozygous Rats............................................................................................................ 35 3.1. Introduction ........................................................................................................... 35 3.1.1. Hippocampal Electrophysiology in Psychiatric Disease .................................. 35 3.1.2. Calcium Channels & Place-Cells .................................................................... 39 3.1.3. Calcium Channels in Hippocampal Network Activity ...................................... 41 3.1.4. Chapter Aims ................................................................................................. 42 3.2. Methods ................................................................................................................ 43 3.2.1. Behavioural Protocol ...................................................................................... 43 3.2.2. Data Analysis ................................................................................................. 46 3.2.3. Statistical Analysis ......................................................................................... 51 3.3. Results .................................................................................................................. 52 3.3.1. Single-Cell Firing Properties .......................................................................... 52 3.3.2. Behaviour on the Linear Track ....................................................................... 54 3.3.3. Place Cell Properties on the Familiar Linear Track ........................................ 55 3.3.4. Place-Cell Properties in a Novel Track Location ............................................ 60 3.3.5.
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