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Disinhibition at Feedforward Inhibitory Synapses in Hippocampal Area CA1 Induces a Form of Long-Term Potentiation

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Disinhibition at Feedforward Inhibitory Synapses in Hippocampal Area CA1 Induces a Form of Long-Term Potentiation Disinhibition at Feedforward Inhibitory Synapses in Hippocampal Area CA1 Induces a Form of Long-Term Potentiation by John Oliver Heal Ormond A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Cell and Systems Biology University of Toronto © Copyright by John Oliver Heal Ormond (2009) Disinhibition at Feedforward Inhibitory Synapses in Hippocampal Area CA1 Induces a Form of Long-Term Potentiation Doctor of Philosophy (2009). John Oliver Heal Ormond Graduate Department of Cell and Systems Biology, University of Toronto. Abstract One of the central questions of neuroscience research has been how the cellular and molecular components of the brain give rise to complex behaviours. Three major breakthroughs from the past sixty years have made the study of learning and memory central to our understanding of how the brain works. First, the psychologist Donald Hebb proposed that information storage in the brain could occur through the strengthening of the connections between neurons if the strengthening were restricted to neurons that were co-active (Hebb, 1949). Second, Milner and Scoville (1957) showed that the hippocampus is required for the acquisition of new long-term memories for consciously accessible, or declarative, information. Third, Bliss and Lømo (1973) demonstrated that the synapses between neurons in the dentate gyrus of the hippocampus could indeed be potentiated in an activity-dependent manner. Long-term potentiation (LTP) of the glutamatergic synapses in area CA1, the primary output of the hippocampus, has since become the leading model of synaptic plasticity due to its dependence on NMDA receptors (NMDARs), required for spatial and temporal learning in intact animals, and its robust pathway specificity. Using whole-cell recording in hippocampal slices from adult rats, I find that the efficacy of synaptic transmission from CA3 to CA1 can in fact be enhanced without the induction of classic LTP at the glutamatergic inputs. Taking care not to directly stimulate inhibitory fibers, I show that the induction of GABAergic plasticity at feedforward inhibitory inputs in CA1 results in the reduced shunting of excitatory currents, producing a long-term increase in the amplitude of Schaffer collateral-mediated postsynaptic potentials which is dependent on NMDAR activation and is pathway specific. The sharing of these fundamental properties with classic LTP suggests the possibility of a previously unrecognized target for therapeutic intervention in disorders linked to memory deficits, as well as a potentially overlooked site of LTP expression in other areas of the brain. ii Acknowledgements Performing the experiments contained in this dissertation was a challenging and lengthy undertaking, but was also a very rewarding experience thanks to all those who made contributions, both big and small, along the way. First and foremost, I would like to thank my supervisor and mentor of the past 4 and half years, Dr. Melanie Woodin. I came to the lab with an incredibly vague idea of what I wanted to do, and Dr. Woodin initially provided me with the training I needed to get started, and then gave me the freedom and resources to figure out what direction I wanted to go in. She waited patiently for publications to materialize, and when they finally did, she allowed me to participate directly in the submission process, from which I gained very valuable experience that I will no doubt be able to draw upon throughout my career. For many thought provoking discussions (and for putting up with me), I thank my colleagues in the Woodin lab, Trevor Balena and Brooke Acton. Trevor and Brooke always had insightful ideas to offer during both formal meetings and informal discussions in the lab, and I will miss working alongside them. Additionally, I would like to thank all my colleagues in the Peever, Buck, Lovejoy, Yeomans, and Stephenson labs who made the third floor of Ramsay Wright a very pleasant and friendly place to work. For guiding me through the bureaucratic maze of degree completion and graduation, I thank our graduate coordinator Ian Buglass. Lastly, I would like to thank all members of my thesis committee, both for taking time from their very busy schedules, as well as for providing very helpful comments and suggestions, and for always asking very thoughtful and thought-provoking questions. The core members of the committee were Dr. Melanie Woodin, Dr. John Peever, and Dr. Min Zhuo; attending various iii committee meetings in a number of different capacities were Dr. Les Buck and Dr. Richard Stephenson; and joining us from the University of California at Los Angeles was the external examiner Dr. Dean Buonomano. Without their help, I would no doubt have had to live through another Toronto winter! iv Table of Contents Abstract...........................................................................................................................................ii Acknowledgements........................................................................................................................iii Table of Contents............................................................................................................................v Table of Figures............................................................................................................................vii Table of Tables...............................................................................................................................ix 1. General introduction to hippocampal physiology and synaptic plasticity..............................1 1.1 Opening remarks………………………………………………………...1 1.2 Fast and slow synaptic transmission……………………………………2 1.3 The excitatory synapse…………………………………………………..3 1.4 The inhibitory synapse…………………………………………………..5 1.5 Regulation of the driving force for GABAAR currents………...……..7 1.6 Circuitry of the hippocampus…………...……………………………...8 1.7 Long-term potentiation………………………………………………...10 1.8 Involvement of LTP in memory…………………...…………………..14 1.9 Interneurons in the hippocampus……………………………………..14 1.10 Types of interneurons………………………………………………….16 1.11 Feedforward inhibition………………………………………………...17 1.12 Reports of inhibitory plasticity……………………………………...…20 1.13 Hypotheses………………………………………………………………22 2. Disinhibition Mediates a Form of Hippocampal Long-Term Potentiation in Area CA1...20 2.1 Introduction: Feedforward inhibition in CA1......................................24 2.2 Results: Disinhibition increases the efficacy of excitatory transmission............................................................................................ 27 2.3 Figures......................................................................................................32 2.4 Discussion: Disinhibition-mediated long-term potentiation................46 3. A Heterosynaptic Increase in GABAergic Conductance Maintains the Pathway Specificity of Disinhibition-Mediated LTP.............................................................................................51 v 3.1 Introduction: Glutamatergic LTP is pathway specific.........................52 3.2 Results: Heterosynaptic increases in GABAAR synaptic conductance confines LTP to the paired pathway......................................................54 3.3 Figures......................................................................................................59 3.4 Discussion: Both classic and disinhibition-mediated LTP involve the interaction of synapse specific and cell wide plasticity.........................66 4. General discussion of the main findings: A role for disinhibition in memory....................70 4.1 Major conclusions....................................................................................70 4.2 Feedforward inhibition in vivo................................................................72 4.3 Plasticity during theta/gamma and SWRs.............................................79 4.4 Future experiments..................................................................................82 4.5 Final remarks...........................................................................................86 5. Detailed Materials and Methods............................................................................................87 5.1 Ethics approval........................................................................................87 5.2 Slice preparation......................................................................................87 5.3 Electrophysiology.....................................................................................88 5.4 Data analysis.............................................................................................90 5.5 Statistics....................................................................................................90 6. References...............................................................................................................................92 vi Table of Figures Figure 1. Circuitry of the hippocampus. 9 Figure 2. Feedforward inhibition in area CA1. 19 Figure 3. Feedforward inhibition reduces EPSP amplitude. 32 Figure 4. Feedforward inhibition overlaps the EPSP rising phase. 33 Figure 5. EGABA depolarization underlies a large component of mixed LTP. 34 Figure 6. LTP induction leads to simultaneous EGABA depolarization and LTP. 35 Figure 7. APV blocks pairing-induced GABAergic plasticity in single pathway experiments. 36 Figure 8. Depolarization of EGABA
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