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Copyright by Gregory James Ordemann 2021 Copyright by Gregory James Ordemann 2021 The Dissertation Committee for Gregory James Ordemann Certifies that this is the approved version of the following dissertation: Voltage Gated Ion Channel Control of CA1 Pyramidal Neuron Function in Wild Type and fmr1 KO mice Committee: Darrin Brager, Supervisor Nace Golding, Co-supervisor Laura Colgin Daniel Johnston Jonathan Pierce Voltage Gated Ion Channel Control of CA1 Pyramidal Neuron Function in Wild Type and fmr1 KO mice by Gregory James Ordemann Dissertation Presented to the Faculty of the Graduate School of The University of Texas at Austin in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy The University of Texas at Austin May 2021 To my parents For supporting me as I follow my dreams and Being there whenever I need you. To my wife Who has made every day better than the last. Acknowledgements The accomplishments that have brought me to this point are far from mine to claim on my own. I have been surrounded by people, both in and out of the lab, who have guided me and kept me motivated to accomplish the behemoth task of achieving a Ph.D. I came to neuroscience with great interest, and very little experience. I will be forever grateful to Dr. Jonathan Pierce for providing me the opportunity to work as a post-baccalaureate research assistant in his lab. Dr. Brager has been an incredibly supportive, engaged, and enthusiastic mentor from answering my every inane question to listening to me ramble on about far-fetched ideas. Dr. Brager provided me with the training to succeed, the space to allow me to develop as a scientist, and the drive to design and perform experiments with precision and integrity. I have learned and achieved more than I thought was possible, and that is thanks to Dr. Brager’s excellent mentorship. I would like to thank the members of my committee, Drs. Laura Colgin, Nace Golding, Daniel Johnston, and Jonathan Pierce, for their enthusiasm and advice on topics both scientific and otherwise. The lab environment has changed drastically throughout my time at UT, however, the people have always been a positive source of support, feedback, and distraction (when necessary). I would like to thank Drs. Elizabeth Arnold, Federico Brandalise, Brian Kalmbach, Ruchi Malik, Raymond Chitwood, Jennifer Siegel, Chung Sub Kim, and Niraj Desai, and Megan Volquardsen, Christopher Apgar, and Brandy Routh for being incredible lab mates. Dr. Richard Gray has been incredibly helpful in teaching me the importance of understanding the equipment I work with, and to be unafraid of diving into a problem head-first to fix it myself. v Dr. Gray and Lauren Hewitt have been incredible friends, creating an environment of camaraderie that has been invaluable in developing a welcoming and collaborative environment in which ideas (and graduate students) can thrive. For that I cannot thank them enough. Thank you to the members of my cohort, Dr. Morgan Hernandez, Matthew Whitmire, and Philip Lambeth, who have been amazing friends and a fantastic support system. I would like to thank and acknowledge the tremendous amount of work done by Krystal Phu and the office staff of the Center for Learning and memory, who work tirelessly to allow graduate students to focus on their lab work. Finally, I would like to thank my family. My parents instilled in me the drive and confidence to pursue my goals, while providing love and support at every step along the way. I could not ask for better siblings, who are also some of my best friends. Thank you for keeping me from taking myself too seriously and for bringing me back to reality when I need it. To my wife, who has been willing to listen to and discuss every success and failure along the way. Thank you for being there for me every time, whether I ask or not. vi Voltage Gated Ion Channel Control of CA1 Pyramidal Neuron Function in Wild Type and fmr1 KO mice Gregory James Ordemann, Ph.D. The University of Texas at Austin, 2021 Supervisor: Darrin Brager Co-Supervisor: Nace Golding Changes in the complement or function of ion channels can drastically affect individual neurons and their constituent circuits. Neuron function is a highly tunable system. The difference between function and dysfunction can exist on a razor’s edge. Studying neurons in disease can provide insight into the operation of brain structures. This dissertation focuses on ion channel control over individual neuron and neuronal circuit function of CA1 pyramidal neurons in wild type mice and a model of Fragile X syndrome. Using somatic recordings, we investigated differences in CA1 pyramidal neurons across the dorsoventral axis of mouse hippocampus. Ventral neurons show depolarized resting Vm, have greater RN, and have reduced dendritic branching compared with dorsal neurons. Action potential firing was not different across the dorsoventral axis of mouse hippocampus. However, ventral neurons have a more depolarized action potential threshold compared to dorsal neurons. Action potential threshold in ventral neurons was more sensitive to block of KV1 channels compared to dorsal neurons. Outside-out voltage clamp recordings showed larger slowly inactivating K+ vii currents in ventral neurons. Despite differences in subthreshold properties between dorsal and ventral CA1 neurons, action potential output is normalized by the differential functional expression of D-type K+ channels. In investigating the effects of fmr1 KO on CA1 pyramidal neurons no difference was identified in intrinsic function across the dorsoventral axis of mouse hippocampus between wild type and fmr1 KO neurons. We further investigated differences in wild type and fmr1 KO CA1 neurons using somatic and dendritic recordings to investigate synaptic transmission at distal inputs from entorhinal cortex. We found that TA-LTP was impaired in male fmr1 KO mice. Synaptically evoked dendritic Ca2+ signals were smaller in fmr1 KO neurons. Threshold for Na+ dependent dspikes was depolarized in fmr1 KO mice. Dspike threshold and TA-LTP were restored by block of A-type K+ channels. TA-LTP impairment, coupled with previously described enhanced Schaffer collateral LTP, may contribute to spatial memory alterations in FXS. Furthermore, as both of these LTP phenotypes are attributed to changes in A-type K+ channels in FXS, our findings provide a potential therapeutic target to treat cognitive impairments in FXS. viii Table of Contents List of Tables ....................................................................................................................... x List of Figures .................................................................................................................... xi Chapter 1: Introduction .................................................................................................... 1 Chapter 2: D-type K+ channels normalize action potential firing between dorsal and ventral CA1 pyramidal neurons of the mouse hippocampus ................. 62 Chapter 3: Intrinsic properties of dorsal and ventral fmr1 KO CA1 pyramidal neurons ......................................................................................................... 94 Chapter 4: Impaired long-term potentiation and synaptically evoked Ca2+ signaling in the TA pathway in a mouse model of Fragile X syndrome ................... 109 Chapter 5: Altered A-type K+ channel function impairs dendritic spike initiation and TA LTP in Fragile X syndrome ........................................................... 127 Chapter 6: Discussion .................................................................................................. 164 Appendix: Methods ...................................................................................................... 169 References ....................................................................................................................... 179 ix List of Tables Table 3.1: Comparison of wild type and fmr1 KO dorsal and ventral CA1 pyramidal neurons ....................................................................................................... 106 x List of Figures Figure 1.1: The action potential model of Hodgkin and Huxley .................................... 12 Figure 1.2: Single channel recordings using the patch clamp method ........................... 26 Figure 1.3: Axon projections in the major excitatory pathways projecting onto CA1 pyramidal neurons within the hippocampus ................................ 29 Figure 1.4: Hypothesized physiology of active dendrites in CA1 pyramidal neurons ... 35 Figure 2.1: Mapping of slice location along the dorsal ventral axis of mouse hippocampus ................................................................................................. 66 Figure 2.2: Subthreshold intrinsic membrane properties in dorsal and ventral CA1 neurons ................................................................................................. 70 Figure 2.3: h-channel and KIR activity does not differ between dorsal and ventral CA1 neurons ..................................................................................... 72 Figure 2.4: Greater dendritic branching in dorsal compared with ventral CA1 pyramidal neurons ............................................................................... 75 Figure 2.5: Action potential threshold is more depolarized in ventral compared with dorsal CA1 neurons ............................................................. 78 Figure 2.6: D-type K+ channel conductance density is higher in ventral compared
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