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Non-Associative Hippocampal Long-Term Depression (LTD) And ,vûaJ-Associ/^r«ue H(^Pocfp^f^nu Lo^6-Tei^r^ C^TD) jWb PfS^ûc\FrriJe ^ o c o ^ r tY U i^ûT^T/mot\J LONG-TERM OF SYNAPTIC TRANSMISSION IN by Gerolemos Christofi A thesis submitted for the degree of Doctor of Philosophy in the University of London Faculty of Science Department of Physiology University College London September 1992 ProQuest Number: 10045542 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10045542 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 ABSTRACT Long term potentiation (LTP) is an enduring, activity-dependent increase in synaptic transmission. Long term depression (LTD) is an enduring, activity-dependent decrease in synaptic transmission. Both phenomena may form the neuronal basis of learning and memory. Intracellular recording in isolated slices of rat brain was used to study (i) associative LTP in somatosensory neocortex, and (ii) non-associative LTD in hippocampus. (i) In layer V cells of neocortex, the incidence of induction of associative LTP was much lower in the slice than reported for the awake cat; this might be explained by the loss of extrinsic noradrenergic activity in the slice. To test this hypothesis, the actions of noradrenaline and the 8 ,-adrenergic receptor agonist, isoprenaline, were investigated on ( 1) membrane properties, and ( 2 ) the probability of induction of associative LTP. The drugs produced a dose-dependent, reversible reduction of spike accommodation and an increase in excitability but had no effect on the depolarising slope or peak amplitude of sub threshold excitatory postsynaptic potentials (EPSPs) evoked by white matter stimulation. The probability of induction of associative LTP was not changed by these drugs, and hence the lower probability in vitro than in vivo cannot be explained solely by the loss of extrinsic noradrenergic activity. (ii) In hippocampal CAl pyramidal neurones, postsynaptic potentials (PSPs) were evoked by test stimulation of stratum radiatum. Conditioning was non-associative and consisted of postsynaptic depolarization and firing, induced by either high frequency antidromic stimulation or postsynaptic injection of depolarizing current pulses. LTD was reliably induced postsynaptically when conditioning was applied during pharmacological block or reduction of synaptic transmission, achieved by transiently bathing slices in a bathing medium containing either a raised [Mg^^], selective glutamate antagonists, or a 7 -aminobutyric acid receptor antagonist. The postsynaptic induction of LTD required extracellular Ca^^. Measurements of resting and activity-dependent increases in cytosolic [Ca^^] were made using the fluorescent Ca^"^ indicator FURA-2 iontophoresed into the cell to elucidate the conditions required for LTD induction. Possible reasons why the pharmacological reduction of synaptic transmission during conditioning stimuli could facilitate LTD induction are discussed. DEDICATION A^IEPOEIE Il/o6ç Tovç yoveCg fiov ACKNOWLEDGEMENTS I am glad to have the opportunity to express my gratitude to my supervisor, Dr Lynn Bindman, for her patience and encouragement over the last three years. I am grateful to my buddy, Dr Alex ("cor blimey, Guv!") Nowicky for developing the computer programs which helped make the analysis of much of the work possible, and for his support throughout my time at UCL. I would like to thank Dr Stephen Bolsover for allowing me the use of the imaging equipment in his laboratory and for technical advice and help with the Ca^"^-imaging experiments. Dr Michael Duchen, Ms Beverley Clark and Professor Tim Biscoe kindly provided access to computers, when emergencies arose. Many members of Department (both past and present) have provided friendship and general support during my stay at UCL; in particular Vincent O’Connor {aka Jason Cundy), Margaret Carey, Roz Pearce, Beverley Clark, Fatwan Al-Mohanna, Alex "MC" Dougall, Louise Upton, Rob Fern, and Liza Rosser. A special acknowledgement must be made to the Medical Research Council for the award of a Postgraduate Scholarship, without which this work could not have been pursued. The work described in section A of this thesis was conducted during the first year of my training, in collaboration with Dr Alex Nowicky, co-worker in Dr Bindman’s group. I conducted the vast majority of the work described in Section B by myself. For technical reasons, the Ca^'^-imaging experiments (Sections 2.2 and 5.8) were conducted in collaboration with either Dr Alex Nowicky (in the majority of cases). Dr Lynn Bindman, or Dr Stephen Bolsover. TABLE OF CONTENTS TITLE PAGE 1 ABSTRACT 2 DEDICATION AND ACKNOWLEDGEMENTS 3 LIST OF FIGURES 8 TABLES 10 ABBREVIATIONS 11 CHAPTER 1 GENERAL INTRODUCTION PREFACE 13 1.1 Learning and memory 13 The Hebbian synapse 13 1.2 Long-term potentiation 14 Methods of LTP induction 15 LTP - A neural substrate for learning and memory? Possible behavioural correlates 15 Associative LTP and its behavioural correlate 16 1.3 Organization of the hippocampus 17 Cortical Areas 17 Main Cell Types 19 Afferent Fibres 19 Recurrent inhibitory circuits and postsynaptic inhibition 20 The neuronal (tri-synaptic) circuit 21 Lamella 21 1.4 LTP in the hippocampus 21 An induction threshold for LTP in the hippocampus 21 The NMDA receptor and the induction of hippocampal LTP 22 NMDA receptor-dependent LTP 22 NMDA-receptor-independent LTP 24 Calcium and LTP 25 The role of GAB A receptor-mediated inhibition in LTP induction 25 GABA^-mediated inhibition 25 GABAg-mediated inhibition 26 Enhancement of E-S potentiation 26 Expression of hippocampal LTP: presynaptic, postsynaptic or both? 27 Possible presynaptic mechanisms underlying LTP expression 27 Possible postsynaptic mechanisms underlying LTP expression 29 Can quantal analysis of synaptic variability resolve the LTP expression site issue? 30 1.5 LTP in the neocortex 31 Historical background 32 GABA a inhibition and neocortical LTP 32 NMDA receptors and the induction and maintenance of neocortical LTP 32 The associative, postsynaptic induction of LTP in the neocortex 33 Associative LTP in the awake animal 36 Postsynaptic and associative LTP 36 Neuronal transport 36 Postsynaptic conductance changes 37 Associative LTP - some questions 37 SECTION A: INVESTIGATION OF B-ADRENERGIC MODULATION OF SYNAPTIC TRANSMISSION AND ASSOCIATIVE LTP IN SLICES OF RAT SENSORIMOTOR CORTEX 1.6 Introduction 39 1.7 Forebrain noradrenergic connections 39 1.8 Adrenergic receptors in the neocortex 40 1.9 Effects of Noradrenergic agonists on hippocampal regions 42 Dentate gyrus 42 Area CA3 43 Area CAl 44 1.10 Effects of noradrenergic agonists on sensory neocortex 46 1.11 Aims of the investigation 48 SECTION B: LONG-TERM DEPRESSION (LTD) IN THE HIPPOCAMPUS AND NEOCORTEX 1.12 Introduction 50 1.13 Neural network models predict enduring decreases in synaptic transmission 50 1.14 Long-term depression 51 Definitions 51 Associative or homosynaptic LTD in the hippocampus 52 Heterosynaptic LTD in the hippocampus 54 The role of NMDA receptors in homo- and heterosynaptic LTD in the hippocampus 56 Prolonged low-frequency activation of NMDA receptors can induce LTD 57 NMDA-receptor-independent LTD 58 What component of the EPSP is depressed? 59 Factors necessary for the induction of LTD in vitro 59 The ACPD (metabotropic) receptor in LTD 60 1.15 Activity-dependent LTD in the neocortex 60 NMDA receptors and the postsynaptic induction of neocortical LTD 60 The role of Ca^^ in LTD 62 1.16 Aims of the present study 63 CHAPTER 2 MATERIALS AND METHODS 2.1 The postsynaptic induction of non-associative long-term depression (LTD) in rat hippocampal slices 65 Dissection and hippocampal slice preparation 65 Artificial cerebrospinal fluid 6 6 Experimental recording chamber 6 6 Recordings from the submerged hippocampal slice 67 Harp construction 6 8 Electrodes 6 8 Recording electrodes 6 8 Stimulating electrodes 69 Voltage recordings and current injection apparatus 70 Microelectrode support and drive systems 70 Prevention of electrical interference and mechanical vibration 71 Hippocampal slice evaluation 71 Hippocampal recording and stimulation 72 Characterization of passive membrane properties and synaptic responses 76 Conditioning paradigms 76 Induction of hippocampal LTP 76 Induction of hippocampal LTD 77 Drugs 78 Raised magnesium ion bathing solutions 78 Glutamate receptor antagonists 78 7 -amino butyric acid (GABA^) receptor antagonist 79 Analysis of results 79 Measurement of cell stability during and after drug perfusion 80 2.2 Measurements of intracellular Ca^^ using Fura-2 microfluorimetry 80 2.3 Methods for studying synaptic transmission and the postsynaptic induction of LTP in layer V neurones in slices of rat neocortex 83 Dissection and neocortical slice preparation 83 Neocortical recordings in the gas-liquid interface mode 83 2.4 Recording and stimulation 84 Pyramidal cell identification 84 Drugs: Noradrenergic and 6 -agonists 8 6 2.5 The conditioning paradigm 8 6 The postsynaptic induction of neocortical LTP 8 6 Analysis of Results 8 6 SECTION A INVESTIGATION
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