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The Role of Δ Subunit-Containing Γ-Aminobutyric Acid Type a Receptors

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THE ROLE OF δ SUBUNIT-CONTAINING γ-AMINOBUTYRIC ACID TYPE A RECEPTORS IN MEMORY AND SYNAPTIC PLASTICITY by Paul David Whissell A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Institute of Medical Science University of Toronto © Copyright by Paul Whissell, 2014 Paul Whissell The role of δ subunit-containing γ-aminobutyric acid type A receptors in memory and synaptic plasticity Doctor of Philosophy, Institute of Medical Science, University of Toronto, 2014 Abstract Background: Extrasynaptic γ-aminobutyric acid type A receptors that contain the δ subunit (δGABAA receptors) are highly expressed in the dentate gyrus (DG) of the hippocampus, where they generate a tonic conductance that regulates activity. GABAA receptor-dependent signaling regulates memory and neurogenesis in the adult DG; however, the role of δGABAA receptors in these processes is unclear. Accordingly, it was postulated that δGABAA receptors regulate memory and neurogenesis in the DG. Methods: A combination of genetic and pharmacologic techniques was employed. Memory in wild-type (WT) and δ subunit null (Gabrd–/–) mice was assessed using object-place recognition, novel object recognition, contextual discrimination, fear conditioning, fear extinction and water maze tasks. Long-term potentiation, a molecular correlate of memory, was examined using the in vitro hippocampal slice preparation. To ascertain the effects of enhanced δGABAA receptor activity, the receptor-preferring agonist 4,5,6,7- tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP; 4 mg/kg) was applied either as a pre-treatment (2 weeks prior to testing) or an acute treatment (30 min prior to testing). Results: Gabrd–/– mice exhibited impaired object-place recognition, novel object recognition and contextual discrimination relative to WT mice. Further, Gabrd–/– mice exhibited impaired fear extinction, although fear acquisition was enhanced. Pre-treatment with THIP improved memory in WT but not Gabrd–/– mice. Consistent with these behavioural findings, ii neurogenesis was impaired in Gabrd–/– mice and enhanced in WT mice by pre-treatment with THIP. In contrast to the beneficial effects of pre-treatment with THIP, acute THIP impaired memory and long-term potentiation in WT mice. Conclusions: These results indicate that δGABAA receptors promote memory and neurogenesis under baseline conditions. These processes may also be enhanced by long- term activation of δGABAA receptors with selective drugs, provided that these drug are absent during testing. Further, these findings show that acute activation of δGABAA receptors impairs memory and long-term potentiation. Implications: δGABAA receptors may be a therapeutic target for the long-term treatment of memory dysfunction during aging, injury and disease. These findings also have clinical implications, as δGABAA receptors are molecular targets for therapeutic and recreational drugs. The acute amnestic effects of these compounds may be partially explained by δGABAA receptor activity. iii Acknowledgements First and foremost, I would like to thank my supervisor and mentor, Dr. Beverley Orser, for her inspiration, dedication, integrity and patience throughout this auspicious journey. I am grateful to her for setting up an environment where success was not only possible, but also tremendously enjoyable. To all post-doctoral researchers and research associates who came through the lab (including Dian-Shi, Xuanamao, Hongbin, Michael, Sinziana, and Antonello) I would like to extend my thanks for their expertise, advice and uncompromising standards. A special thanks goes to Dian-Shi for doing it all with a smile. I am also very grateful to all Orser lab students (brothers- and sisters-in-arms). I would like to thank Loren, Rob, Agnes, Irene, Anine, Will and Dave for making research fun, thought-provoking and productive. I would like to personally thank Irene for her patience in enduring a painful saga of experiments that never seemed to end. To the Physiology student community, I'm grateful for the support, lunch room timbits and all the journal club cookies. To the summer students (Erica, Zeenia, Eric, Michael, Dave, Bonnie and Jane) I would like to say thanks for reminding me why I got into research. I'd like to thank the technical staff (Ella and Yao-Fang) as well as my committee members (Dr. Wojtowicz, Dr. Zhang, Dr. Feng, Dr. Yeomans, Dr. Frankland, Dr. Osborne and Dr. Smith) for their support and input. I'm particularly indebted to Dr. Wojtowicz and Shira Rosenzweig for the opportunity to be involved in such an exciting collaboration. Finally, I'd like to thank my girlfriend Heather, my family (4 brothers, 1 sister, 2 nieces and 1 nephew) and my mother, Dr. Cynthia Whissell, for being awesome. iv List of Contributors The majority of Chapter 4 was derived from the article, "δGABAA receptors promote memory and neurogenesis" in the journal Annals of Neurology (Whissell et al. 2013), which was the work of several investigators. I served as co-first author of this paper along with Dr. Shira Rosenzweig. Other authors include Irene Lecker (Ph.D. candidate), Dr. Dian-Shi Wang, Dr. Beverley Orser and Dr. J. Martin Wojtowicz. Irene Lecker also contributed to several behavioural experiments (Figure 4.6, Figure 4.7) by handling animals and performing drug injections. Dr. Rosenzweig collected and analyzed all data relating to neurogenesis (Figure 4.8, Figure 4.9) with the assistance of technician Yao-Fang Tan. Portions of this data have been presented previously (Rosenzweig 2011) but have not been published. I contributed to the presentation and interpretation of this data for the paper. Finally, Dr. Wang, Dr. Orser and Dr. Wojtowicz contributed to the writing of the paper. Technician Ella Czerwinska (M. Sc.) managed the animal population used in this study. The majority of Chapter 5 was derived from the article, "Acute activation of δGABAA receptors impairs memory and synaptic plasticity in the hippocampus" that is currently under review for publication in Frontiers in Neural Circuits. I served as first author of this paper. Other authors include Dave Eng (M.Sc.), Irene Lecker, Dr. Loren Martin, Dr. Wang and Dr. Orser. Dave Eng performed several behavioural experiments (Figure 5.1C, Figure 5.2B and Figure 5.2C) which are partly documented in his thesis (Eng 2008) but have not been published. I contributed to the collection, analysis and presentation of this data. Irene Lecker contributed to behavioural experiments by handling animals and performing drug injections (Figure 5.3) while the remaining authors contributed to writing. Technician Ella Czerwinska again managed the animal population used. v Table of Contents Abstract ..................................................................................................................................... ii Acknowledgements .................................................................................................................. iv List of Contributors .................................................................................................................... v Table of Contents .................................................................................................................... vi List of Figures .......................................................................................................................... ix List of Tables ...........................................................................................................................xii List of Abbreviations................................................................................................................ xiii Chapter 1. Thesis Structure ...................................................................................................... 1 1.1. Chapter Structure ....................................................................................................... 1 1.2. Overview ..................................................................................................................... 1 1.3. Hypothesis .................................................................................................................. 4 1.4. Specific aims............................................................................................................... 4 1.5. Results ........................................................................................................................ 4 1.6. Conclusions ................................................................................................................ 5 1.7. Implications ................................................................................................................. 5 Chapter 2. Introduction ............................................................................................................. 7 2.1. Overview ..................................................................................................................... 7 2.2. GABA .......................................................................................................................... 7 2.3. GABAA receptors ...................................................................................................... 11 2.4. GABA activation of GABAA receptor channels .......................................................... 34 vi 2.5. The hippocampal formation and memory ................................................................. 43 2.6. Anatomy of the hippocampal formation ...................................................................
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