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Containing Γ-Aminobutyric Acid Subtype a Receptors in Learning and Synaptic Plasticity

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Containing Γ-Aminobutyric Acid Subtype a Receptors in Learning and Synaptic Plasticity THE REGULATORY PROPERTIES OF α5 SUBUNIT- CONTAINING γ-AMINOBUTYRIC ACID SUBTYPE A RECEPTORS IN LEARNING AND SYNAPTIC PLASTICITY by Loren John Martin A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Institute of Medical Science University of Toronto © Copyright by Loren Martin, 2009 The Regulatory Properties of α5 Containing γ-Aminobutyric Acid Subtype A Receptors in Learning and Synaptic Plasticity Loren Martin Doctor of Philosophy Institute of Medical Science University of Toronto 2009 Abstract Synaptic plasticity, which is thought to represent the neuronal substrate for learning and memory is influenced by the degree of GABAergic inhibitory tone. In particular, γ-aminobutyric acid subtype A receptors (GABAARs), which mediate the majority of inhibitory neurotransmission in the mammalian brain regulate learning and plasticity. In these studies I examined a subpopulation of α5 subunit-containing GABAA receptors (α5GABAARs), which are preferentially expressed in the hippocampus, to determine whether they have a specific role in memory processes. I hypothesized that α5GABAAR-activity constrains hippocampus-dependent learning and CA1 synaptic plasticity. The main research objective of this thesis was to investigate the electrophysiological changes within the hippocampus that accompany genetic and pharmacological targeting of α5GABAARs and how these changes impact behaviour. I found that the general anesthetic etomidate enhanced a tonic inhibitory conductance generated by α5GABAARs, and this action correlated with an impairment of long-term potentiation (LTP) and hippocampus-dependent memory performance for fear-associated memory and spatial navigation. Mice with a genetic deletion of the α5 subunit gene (Gabra5–/–) were resistant to the LTP- and memory-impairing effects of etomidate. Additionally, the LTP- and memory-impairing effects of etomidate were rescued by pharmacologically inhibiting α5GABAARs. Genetic and ii pharmacological inhibition of α5GABAARs enhanced associative learning in trace fear but not contextual fear conditioning tasks. Interestingly, genetic deletion and pharmacological inhibition of α5GABAARs did not result in the common adverse side-effects associated with non-selective inhibition of GABAARs such as anxiogenesis or seizures. Further, I found that blocking the tonic inhibition generated by α5GABAARs lowered the threshold for LTP, such that lower stimulation frequencies enhanced LTP. Synaptic changes within this frequency band were modified independently of phasic GABAAR inhibition. Inhibiting the α5GABAAR-dependent membrane conductance was associated with an increase in the depolarizing envelope during 10 Hz stimulation. These experiments provide new insights into the in vitro and in vivo physiology of α5GABAARs and suggest that a tonic inhibition generated by α5GABAARs constrains learning and glutamate plasticity through regulation of the membrane’s electrical properties. iii Acknowledgments I thank Dr. Beverley Orser for her continuous support and guidance over the last 5 years. Her infectious enthusiasm for science and unparalleled work ethic have truly been an inspiration. I also thank my thesis and examining committee members Drs. Mike Salter, John Roder, Zhengping Jia, Harold Atwood, Paul Frankland and Michael Fanselow (UCLA). Thanks also to Drs. John Macdonald and Mike Jackson for helpful discussions and technical contributions. I am grateful for the contributions of the Orser lab. I thank Ella Czerwinska, Rob Bonin, Agnieszka Zurek and Paul Whissell for making the lab a fun place in which to work. Their participation in theoretical discussions and grammatical corrections were greatly appreciated. A special acknowledgment must also go to those whose emotional support never wavered – my family. First my parents, Carol and Wayne for enduring my 11 year academic adventure, my sister Lori-Ann and my wife Marianne for her love, tolerance, understanding and help. List of Contributions Several investigators assisted with the experiments reported in this thesis. In Chapter 4, V.Y. Cheng assisted with the data collection for the Morris water maze, and the drug injections for the fear conditioning, rotarod and open field experiments. In Chapter 5, G.H. Oh assisted with the data collection for the Morris water maze, and drug injections for the fear conditioning experiments. In Chapter 6, Dr. William Ju contributed the Western Immunoblots for the glutamate receptors. In Appendix 1, R.P. Bonin completed the tonic inhibitory recordings in cultured hippocampal neurons. This work could not have been completed without the financial support provided to me by the Canadian Institutes of Health Research and the Ontario Graduate Scholarship program. iv Table of Contents Abstract............................................................................................................................................ii Acknowledgments ..........................................................................................................................iv Table of Contents ............................................................................................................................v List of Figures.................................................................................................................................xi List of Abbreviations....................................................................................................................xiii Chapter 1. Thesis Structure ............................................................................................................1 1.1 General overview.................................................................................................................1 1.2 General hypothesis and thesis questions .............................................................................4 1.3 Thesis structure....................................................................................................................5 Chapter 2. General Introduction.....................................................................................................7 2.1 The hippocampus.................................................................................................................7 2.1.1 Gross structural overview........................................................................................7 2.1.2 Circuitry...................................................................................................................8 2.1.3 Laminar organization and neurotransmitter systems...............................................9 2.1.4 Learning, performance and hippocampus-dependent tasks...................................18 2.2 Modifications of synaptic connections..............................................................................23 2.2.1 Long-term potentiation: Properties and characteristics.........................................24 2.2.2 Long-term depression............................................................................................27 2.2.3 Bidirectional modification of synaptic plasticity ..................................................29 2.2.4 Role of GABA receptors in the induction of NMDA-dependent LTP..................33 2.3 GABA and GABAA receptor-mediated inhibitory neurotransmission..............................34 2.3.1 Synthesis and metabolism of GABA.....................................................................34 2.3.2 GABAA receptor-mediated hyperpolarization and shunting inhibition ................35 2.3.3 General overview of GABAA receptors ................................................................39 v 2.3.4 Location and physiological role of α5GABAAR subunits ....................................47 2.3.5 Pharmacology of α5GABAAR subunits................................................................54 2.3.6 α5GABAA receptors as a candidate target for the modification of hippocampus-dependent learning and synaptic plasticity .....................................57 2.3.7 A role for α5GABAARs in neurological disorders................................................63 2.4 Anesthesia..........................................................................................................................68 2.4.1 In vitro actions of general anesthetics ...................................................................69 2.4.2 Action of anesthetics on LTP and memory ...........................................................71 2.4.3 Problems associated with anesthetic-induced amnesia .........................................72 2.4.4 Intraoperative awareness and post-operative cognitive dysfunction.....................73 2.5 Summary............................................................................................................................75 Chapter 3. General Methods and Materials..................................................................................77 3.1 Experimental animals ........................................................................................................77 3.2 Electrophysiology..............................................................................................................78 3.2.1 Preparation of hippocampus tissue slices..............................................................78 3.2.2 Extracellular synaptic stimulation .........................................................................79 3.2.3 Extracellular field recordings ................................................................................79
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