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Studies on the Asynchronous Synaptic Responses and Endogenous STUDIES ON THE ASYNCHRONOUS SYNAPTIC RESPONSES AND ENDOGENOUS POTENTIATING SUBSTANCES OF NEUROTRANSMISSION IN THE HIPPOCAMPUS By SANIKA SAMUEL CHIRWA B.Sc, (Pharmacy), The University of British Columbia, 1981 M.Sc, (Pharmarmacology & Therapeutics.). The University of British Columbia, 1985 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Department of Pharmacology & Therapeutics, Faculty of Medicine, The University of British Columbia) We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA 1988 September ©Sanika Samuel Chirwa, 1988 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of Pharmacology and Therapeutics The University of British Columbia Vancouver, Canada Date 26 September 1988 DE-6 (2/88) CHIRWA ii ABSTRACT In the hippocampus, transient tetanic stimulations of inputs, or brief simultaneous pairings of conditioning intracellular postsynaptic depolariz• ations with activated presynaptic afferents at low stimulation frequencies, result in input specific long-term potentiation (LTP) of synaptic transmis• sion. LTP lasts for hours in vitro, or weeks in vivo, and it is thought to be involved in memory and learning. Experimental evidence in the literature suggests that postsynaptic mechanisms mediate LTP induction, whereas presyn• aptic mechanisms are involved in its maintenance. Since LTP is thought to be generated by postsynaptic mechanisms and to be subsequently maintained by presynaptic processes, this suggests the presence of feedback interactions during LTP development, however, the experimental evidence for such inter• actions is presently not available. Consequently, the present studies were conducted to examine possible feedback interactions between postsynaptic and presynaptic elements in the hippocampus. Furthermore, the experiments tested the hypothesis that substances released during tetanic stimulations caused the release of endogenous substances that interacted with activated afferents resulting in alterations in presynaptic functions and LTP produc• tion. Experiments were conducted using transversely sectioned guinea pig hippocampal slices. Briefly, physiological medium containing 3.5 mNi Ba++ and 0.5 mM Ca (denoted as Ba medium) was used to induce the asyn• chronous release of transmitters, observed as evoked miniature EPSPs (minEPSPs) in CA^b neurons after stimulation of the stratum radiatum. During transient Ba++ applications, short bursts of evoked minEPSPs were CHIKWA iii observed following stimulations of the stratum radiatum or conditioning depolarizing current injections into CA^b neurons. Moreover, the frequen• cies of minEPSPs were significantly increased immediately after simultaneous stimulations of the stratum radiatum and conditioning depolarizing current injections into CA^ neurons. Significant increases in the frequencies of evoked minEPSPs were also observed during LTP induced by tetanic stimula• tions. The above increases in the frequencies of evoked minEPSPs were attributed, in part, to presynaptic changes resulting in increases in trans• mitters released. However, a thorough quanta! analysis is requirea to substantiate this conclusion. In order to determine whether any substances released during tetanic stimulations were involved in the mooulation of presynaptic functions and induction of LTP, samples were collected from guinea pig hippocampus and rabbit neocortex. It was found that samples that were collected during tetanic stimulations of the guinea pig hippocampus in vivo or rabbit neocor• tex in vivo produced LTP in the guinea pig hippocampal slice in vitro. Applications of these samples after heating and cooling failed to induce LTP. Subsequent studies demonstrated that PC-12 cells incubated in growth medium treated with samples collected during tetanic stimulations of the rabbit neocortex developed extensive neurite growths. In contrast, PC-12 cell cultures incubated in (1) heated and cooled samples, (2) samples collected in the absence of tetanic stimulations of the rabbit neocortex, or (3) plain growth medium, failed to develop neurite growths. In addition, PC-12 cell cultures that were incubatea in growth medium containing samples collected during tetanic stimulations plus saccharin (10 mM), a substance known to inhibit N6F-dependent neurite growth, failed to develop neurites. CHIRwA iv In separate experiments it was found that saccharin could block (1) the synaptic potentiating effects of the above collected and applied endogenous substances, and (2) LTP induced with tetanic stimulations, in the guinea pig hippocampus in vitro. The concentrations of saccharin used in these studies had insignificant effects on resting membrane potentials, input resistances, spontaneous or evoked responses of CA^b neurons. Furthermore, CA^ neuronal depolarizations induced by N-methyl-DL-aspartate (NMDA) or with tetanic stimulations of the stratum radiatum, were not altered by saccharin applications. In addition, saccharin had insignificant effects on paired- pulse facilitation, post-tetanic potentiations, minEPSP frequencies in CA^ neurons, and Schaffer collaterals terminal excitability. These results suggest that saccharin blocked LTP through mechanisms different from either non-specific alterations in CA^ cell properties or NMDA receptor activation. Perhaps the agent antagonized LTP at a step beyond NMDA receptor activation. That saccharin blocked LTP caused by the applied neocortical sample as well as by tetanic stimulation of the stratum radia• tum, and that saccharin also blocked neurite growth in PC-12 cells induced by the neocortical samples, raises the prospect that growth related substances are involved in LTP generation. In other control experiments, it was found that the potentiating effects of the collected endogenous substances were not antagonised by atropine or dihydro-e-erythroidine. Heated and then cooled solutions of glutamate (a putative transmitter at the Schaffer col laterals-CA^ synapses) still maintained their actions on the CAj^ population spike. While brief applications of 2.5 yg/ml exogenous NGF (from Vipera lebetina) during low frequency stimulations of the stratum CHIKWA v radiatum did not consistently induce LTP, this peptide significantly facili• tated the development of LTP when applied in association with tetanic stimu• lations of weak inputs in the CA^ area. These weak inputs could not support LTP if tetanized in the absence of the exogenous NGF. The results of the studies in this thesis suggested that postsynaptic depolarizations modulated presynaptic functions in the hippocampus. Tetanic stimulations in hippocampus and neocortex caused the release of diffusible substances, which were probably growth related macromolecules, that inter• acted with activated presynaptic afferents and/or subsynaptic dendritic elements resulting in LTP development. The precise locus of actions of these agents awaits further investigations. Research Supervisor CHIRWA vi TABLE OF CONTENTS Chapter Title Page No. A. TITLE PAGE i B. ABSTRACT ii C. TABLE OF CONTENTS vi D. LIST OF TABLES xiv E. LIST OF FIGURES xv F. ABBREVIATIONS xviii G. ACKNOWLEDGEMENTS xix H. DEDICATION xx I. INTRODUCTION 1 2. BASIC MORPHOLOGY OF THE HIPPOCAMPAL FORMATION 8 2.1 General 8 2.2 The hippocampal region 8 2.3 The hippocampus 9 2.4 The dentate gyrus 9 2.5 The hilus and CA^ region 11 2.6 The cornu ammonis field 11 3. CELLULAR PROPERTIES AND INTRINSIC CIRCUITRY 13 3.1 Dentate gyrus granule cells 13 3.2 Cornu ammonis pyramidal neurons 13 3.2.1 Subfield CAX 14 3.2.2 Subfield CA3 15 3.2.3 Subfield CA0 17 CHIRWA vii Chapter Title Page No. 3.3 CA^ and Hi 1 us neurons 18 3.4 Interneurons 19 4. EXTRINSIC AFFERENTS TO THE HIPPOCAMPUS 21 4.1 Entorhinal-hippocampal inputs 21 4.2 Septo-hippocampal inputs 21 4.3 Miscellaneous inputs 22 5. ELECTROPHYSIOLOGY OF THE HIPPOCAMPUS 23 5.1 Electrical properties of neurons 23 5.2 Intrinsic ionic conductances 24 5.3 Bursting activity 25 5.4 Miniature postsynaptic potentials 26 5.5 Evoked field responses 26 5.6 Inhibitory postsynaptic potentials 27 5.7 Electrotonic couplings 29 5.8 Ephaptic interactions 30 6. SYNAPTIC PHARMACOLOGY OF THE HIPPOCAMPUS 31 6.1 GABA 31 6.2 GABAA receptors 31 6.3 GABAB receptors 32 6.4 Putative excitatory transmitters 33 6.5 Exogenous glutamate actions in hippocampus 34 6.6 NMDA and Quisqualate/Kainate receptors 34 6.7 Subsynaptic receptors 35 6.8 Other putative transmitters 36 6.9 Neuromodulators 37 CHIRWA viii Chapter Title Page No. 7. LONG-TERM POTENTIATION IN THE HIPPOCAMPUS 38 7.1 Introduction 38 7.2 Basic features of long-term potentiation 38 7.2.1 Long-term potentiation 38 7.2.2 Distribution of LTP 40 7.2.3 Homosynaptic and heterosynaptic LTP 40 7.2.4 LTP in single neurons 41 7.3 Production of LTP 41 7.3.1 Induction 41 7.3.2 Co-operative LTP 43 7.3.3 Associative LTP 43 7.3.4 Coupled LTP 44 7.4 LTP production with pharmacological methods 44 7.4.1 Raised extracellular K+ 44 7.4.2 Raised extracellular Ca++ 45 7.4.3 Phorbol esters 46 7.4.4 Mast cell degranulating peptides 47 7.4.5 Glutamate 47 7.4.6 Miscellaneous 48 7.5 Blockade of LTP induction 48 7.6 Maintenance of LTP 49 7.6.1 Biochemical and structural changes 49 7.6.2 Protein kinase C 51 7.b.3 Increased transmitter release 51 CHIRWA ix Chapter Title Page No. 7.7 Summary 53 8. BARIUM AND SACCHARIN AS EXPERIMENTAL TOOLS 55 8.1 General 55 8.2 Barium 55 8.2.1 Chemistry 55 8.2.2 Transmitter release 56 8.2.3 K+ currents 57 8.3 Saccharin 58 8.3.1 Chemistry 58 8.3.2 Disposition 59 8.3.3 Tumor promoter 59 8.3.4 Neurite growth 61 8.3.5 Inhibition of enzymes 62 9.
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