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Intrinsic association constants were determined for a series of aminopyridines on phosphatidylserine vesicles, through determination of electrophoretic mobility. The magnitudes of the constants were such that depolarization of the nerve terminal through binding to negative phospholipids seems unlikely to occur. The aminopyridines all had association constants between one half and one sixtieth the association constant of calcium. The aminopyridines probably block potassium channels in their enhancement of synaptic transmission. An interesting correlation was noted in that the ranking of the aminopyridines in terms of their affinity for these lipids was approximately the same as the ranking of their enhancement of synaptic transmission in a wide variety of biological preparations. A possible mechanism for this correlation is that adsorption of these drugs 2 to lipid membranes is the initial and rate-limiting step in their action.

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

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by Hu Xiao Ling. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references (leaves 103-111). / Abstracts in English and Chinese. / Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Basic Physiology of the Nervous System --- p.1 / Chapter 1.1.1 --- Membrane Potential and Its Propagation --- p.2 / Chapter 1.1.2 --- Cellular Communication --- p.3 / Chapter 1.2 --- Background of Neural Modeling --- p.5 / Chapter 1.2.1 --- Models for Membrane --- p.5 / Chapter 1.2.2 --- The Models for Gap Junctions --- p.9 / Chapter 1.2.3 --- A Study on the Pulse Train --- p.11 / Chapter 1.3 --- Main Purposes of the Study --- p.14 / Chapter 1.4 --- Organization of Thesis --- p.15 / Chapter 2 --- Electrical Synaptic Model --- p.17 / Chapter 2.1 --- Introduction --- p.17 / Chapter 2.2 --- Model Description --- p.19 / Chapter 2.2.1 --- An Introduction of the Active Membrane Model --- p.19 / Chapter 2.2.2 --- The Electrical Synaptic Model --- p.25 / Chapter 2.3 --- Numerical Calculation --- p.32 / Chapter 2.4 --- Simulation Results --- p.37 / Chapter 2.5 --- Discussion --- p.44 / Chapter 3 --- Analysis of the Synaptic Model --- p.46 / Chapter 3.1 --- Introduction --- p.46 / Chapter 3.2 --- Time Constant Analysis --- p.48 / Chapter 3.2.1 --- Junctional Time Constant in Bennette's Model --- p.48 / Chapter 3.2.2 --- The Junctional Time Constant in Our Model --- p.52 / Chapter 3.3 --- Model Reconstruction --- p.57 / Chapter 3.4 --- Discussion --- p.62 / Chapter 4 --- Action Potential Train Transmission Analysis --- p.69 / Chapter 4.1 --- Theoretical Analysis on the Refractory Period at the Post-membrane --- p.70 / Chapter 4.1.1 --- Introduction of Membrane Threshold and Refractory Period --- p.71 / Chapter 4.1.2 --- Stochastic Models of Neuron Firing --- p.73 / Chapter 4.1.3 --- Effect of Refractory Period on the p.d.f. of Poisson Process --- p.78 / Chapter 4.2 --- Simulation of the Action Potential Train Transmission --- p.85 / Chapter 4.2.1 --- Effects of the Model Parameter on the Action Potential Train Transmission --- p.90 / Chapter 4.2.2 --- Effects of the Refractory Period of the Post-membrane on the Action Potential Train Transmission --- p.94 / Chapter 4.3 --- Results --- p.96 / Chapter 4.3.1 --- Section Summary --- p.98 / Chapter 5 --- Conclusions and Future Studies --- p.99 / Chapter 5.1 --- Conclusions of Major Contributions --- p.99 / Chapter 5.2 --- Topics for Future Studies --- p.101

Thesis. 1977. Ph.D.--Massachusetts Institute of Technology. Dept. of Electrical Engineering and Computer Science. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND ENGINEERING. / Vita. / Bibliography : leaves 175-184. / Ph.D.

This thesis describes the design, synthesis and development of fluorescent probes to monitor synaptic transmission at individual presynaptic terminals in the mouse brain. Two distinct approaches to accomplish this are discussed. The first approach seeks to monitor synaptic activity by using pH-sensitive endocytic membrane probes to label active presynaptic terminals. The second approach seeks to monitor synaptic activity by loading small fluorescent molecules into presynaptic vesicles and studying their evoked release upon stimulation. The first chapter of this thesis describes currently available techniques that are used to study synaptic transmission in the brain. The use of electrochemical techniques is discussed and the use of fluorescent reporters is introduced as a means to image single synapses with high resolution. Chapter II of this thesis describes the rational design of pH-sensitive membrane probes for labeling recycling vesicles. The synthesis, photophysical properties and biological characterization of these probes are described. Although these probes proved to be too lipophilic to work well in the brain tissue and neuronal culture, their use on the cell surface is demonstrated. Furthermore, the structure activity relationship established by this library of probes can be used to direct the future development of pH-sensing endocytic dyes. Chapter III and IV of this thesis describe the development of new generations of Fluorescent False Neurotransmitters (FFNs) for imaging vesicular content release from individual presynaptic terminals in the brain. Chapter III introduces a novel imaging agent, FFN200, for monitoring and quantifying dopamine release from individual synaptic terminals in the mouse brain. Chapter IV describes the exploration and screening of small fluorescent molecules in the mouse brain for the purpose of developing FFNs at synaptic terminals other than dopamine. FFN7122 is introduced as the first FFN to be developed for terminals outside of dopamine. FFN7122 is shown to be a marker for glutamatergic terminals in the hippocampus, dorsal striatum, and motor cortex of the mouse brain. The evoked release of this probe from presynaptic vesicles is demonstrated and two hypotheses for its uptake mechanism are proposed.

Miniature neurotransmission is the trans-synaptic process where single synaptic vesicles spontaneously released from presynaptic neurons induce miniature postsynaptic potentials. Since their discovery over 60 years ago, miniature events have been found at every chemical synapse studied. However, the in vivo necessity for these small-amplitude events has remained enigmatic. In this thesis, I show that miniature neurotransmission is required for the normal structural maturation of Drosophila glutamatergic synapses in a developmental role that is not shared by evoked neurotransmission. Conversely, I find that increasing miniature events is sufficient to induce synaptic terminal growth. I show that miniature neurotransmission acts locally at terminals to regulate synapse maturation via a Trio guanine nucleotide exchange factor (GEF) and Rac1 GTPase molecular signaling pathway. My thesis study establishes that miniature neurotransmission, a universal but often-overlooked feature of synapses, has unique and essential functions in vivo.

Neurons rely on precise spatial and temporal control of neurotransmitter release to ensure proper communication. Neurotransmission occurs when synaptic vesicles in the presynaptic compartment fuse with the plasma membrane and release their contents into the synaptic cleft, where neurotransmitters bind to receptors on the postsynaptic neuron. Synaptic vesicle pools must maintain a functional repertoire of proteins in order to efficiently release neurotransmitter. Indeed, the accumulation of old or damaged proteins on synaptic vesicle membranes is linked to synaptic dysfunction and neurodegeneration. Despite the importance of synaptic vesicle protein turnover for neuronal health, the molecular mechanisms underlying this process are unknown. In this thesis, we present work that uncovers key components that regulate synaptic vesicle degradation. Specifically, we identify a pathway that mediates the activity-dependent turnover of a subset of synaptic vesicle membrane proteins in mammalian neurons. This pathway requires the synaptic vesicle-associated GTPase Rab35, the ESCRT machinery, and synaptic vesicle protein ubiquitination. We further demonstrate that neuronal activity stimulates synaptic vesicle protein turnover by inducing Rab35 activation and binding to the ESCRT-0 component Hrs, which we have identified as a novel Rab35 effector. These actions recruit the downstream ESCRT machinery to synaptic vesicle pools, thereby initiating synaptic vesicle protein degradation via the ESCRT pathway. Interestingly, we find that not all synaptic vesicle proteins are degraded by this mechanism, suggesting that synaptic vesicles are not degraded as units, but rather that SV proteins are degraded individually or in subsets. Moreover, we find that lysine-63 ubiquitination of VAMP2 is required for its degradation, and we identify an E3 ubiquitin ligase, RNF167, that is responsible for this activity. Our findings show that RNF167 and the Rab35/ESCRT pathway facilitate the removal of specific proteins from synaptic vesicle pools, thereby maintaining presynaptic protein homeostasis. Overall, our studies provide novel mechanistic insight into the coupling of neuronal activity with synaptic vesicle protein degradation, and implicate ubiquitination as a major regulator in maintaining functional synaptic vesicle pools. These findings will facilitate future studies determining the effects of perturbations to synaptic homeostasis in neuronal dysfunction and degeneration.