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Tableau d’honneur de la Faculté des études supérieures et postdoctorales, 2004-2005 / Le noyau réticulaire thalamique (RE) est une structure qui engendre des fuseaux, une oscillation bioélectrique de marque pendant les stades précoces du sommeil. De multiples propriétés neuronales, intrinsèques et synaptiques, sont impliquées dans la génération, la propagation, le maintien et la terminaison des ondes en fuseaux. D’un autre côté, ce rythme constitue un état spécial de l’activité du réseau qui est généré par le réseau lui-même et affecte les propriétés cellulaires du noyau RE. Cette étude se concentre sur ces sujets: comment les propriétés cellulaires et les propriétés du réseau sont inter-reliées et interagissent pour engendrer les ondes fuseaux dans les neurones du RE et leurs cibles, les neurones thalamocorticaux. La présente thèse fournit de nouvelles évidences montrant le rôle fondamental joué par les neurones du noyau RE dans la genèse des ondes en fuseaux, dû aux synapses chimiques établies par ces neurones. La propagation et la synchronisation de l’activité sont modulées par les synapses électriques entre les neurones réticulaires thalamiques, mais aussi par les composantes dépolarisantes secondaires des réponses synaptiques évoquées par le cortex. De plus, la forme générale et la terminaison des oscillations thalamiques sont probablement contrôlées en grande partie par les neurones du RE, lesquels expriment une conductance intrinsèque leurs procurant une membrane avec un comportement bistable. Finalement, les oscillations thalamiques en fuseaux sont aussi capables de moduler les propriétés membranaires et l’activité des neurones individuels du RE. / The thalamic reticular nucleus (RE) is a key structure related to spindles, a hallmark bioelectrical oscillation during early stages of sleep. Multiple neuronal properties, both intrinsic and synaptic, are implicated in the generation, propagation, maintenance and termination of spindle waves. On the other hand, this rhythm constitutes a special state of network activity, which is generated within, and affects single-cell properties of the RE nucleus. This study is focused on these topics: how cellular and network properties are interrelated and interact to generate spindle waves in the pacemaking RE neurons and their targets, thalamocortical neurons. The present thesis provides new evidence showing the fundamental role played by the RE nucleus in the generation of spindle waves, due to chemical synapses established by its neurons. The propagation and synchronization of activity is modulated by electrical synapses between thalamic reticular neurons, but also by the secondary depolarizing component of cortically-evoked synaptic responses. Additionally, the general shaping and probably the termination of thalamic oscillations could be controlled to a great extent by RE neurons, which express an intrinsic conductance endowing them with membrane bistable behaviour. Finally, thalamic spindle oscillations are also able to modulate the membrane properties and activities of individual RE neurons.

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The amphibian retina is commonly used as a model system for studying function and mechanism of the visual system in electrophysiology, since the neural structure and synaptic mechanism of the amphibian retina are similar to higher vertebrate retinas. I determined the specific subtypes of receptors and channels that are involved in chemical and electrical synapses in the amphibian retina. My study indicates that glycine receptor subunits of GlyRº1, 3 and 4 and glutamate receptor subunit of GluR4 are present in bipolar and amacrine dendrites and axons to conduct chemical synapses in the retinal circuit. I also found that the gap junction channel, pannexin 1a (panx1a), is present in cone-dominated On-bipolar cells and rod-dominated amacrine processes possibly to connect rod-and cone-pathway in the inner retina. In addition, panx1a may form hemi-channels that pass ATP and Ca2+ signals. The findings of my study fill the gap of our knowledge about the subtypes of neurotransmitter receptors and gap junction channels conducting visual information in particular cell types and synaptic areas. / by Yufei Liu. / Thesis (M.S.)--Florida Atlantic University, 2011. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2011. Mode of access: World Wide Web.

Neuronal circuit output is dependent on the embedded synapses’ precise regulation of Ca2+ mediated release of neurotransmitter filled synaptic vesicles (SVs) in response to action potential (AP) depolarizations. A key determinant of SV release is the specific expression, organization, and abundance of voltage gated calcium channel (VGCC) subtypes at presynaptic active zones (AZs). In particular, the relative distance that SVs are coupled to VGCCs at AZs results in two different modes of SV release that dramatically impacts synapse release probability and ultimately the neuronal circuit output. They are: “Ca2+ microdomain,” SV release due to cooperative action of many loosely coupled VGCCs to SVs, or “Ca2+ nanodomain,” SV release due to fewer more tightly coupled VGCCs to SVs. VGCCs are multi-subunit complexes with the pore forming a1 subunit (Cav2.1), the critical determinant of the VGCC subtype kinetics, abundance, and organization at the AZ. Although in central synapses Cav2.2 and Cav2.1 mediate synchronous transmitter release, neurons express multiple VGCC subtypes with differential expression patterns between the cell body and the pre-synapse. The calyx of Held, a giant axosomatic glutamatergic presynaptic terminal that arises from the globular bushy cells (GBC) in the cochlear nucleus, exclusively uses Cav2.1 VGCCs to support the early stages of auditory processing. Due to its experimental accessibility the calyx provides unparalleled opportunities to gain mechanistic insights into Cav2.1 expression, organization, and SV release modes at the presynaptic terminal. Although many molecules are implicated in mediating Cav2.1 expression and SV to VGCC coupling through multiple binding domains on the C-terminus of the Cav2.1 a1 subunit, the underlying fundamental molecular mechanisms remain poorly defined. Here, using viral vector mediated approaches in combination with Cav2.1 conditional knock out transgenic mice, we demonstrate that that there a two independent pathways that control Cav2.1 expression and SV to VGCC coupling at the calyx of Held. These implications for the regulation of synaptic transmission in CNS synapses are discussed. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2016. / FAU Electronic Theses and Dissertations Collection

This thesis describes efforts at the interface of chemistry and neuroscience to design and characterize fluorescent probes capable of tracing neurotransmitters from individual release sites in brain tissue. As part of the Fluorescent False Neurotransmitters (FFNs) program, small organic fluorophores have been developed that undergo uptake into specific presynaptic release sites and synaptic vesicles by utilizing the native protein machinery, which can then be released during neuronal firing. The most advanced generation of FFNs are pH-sensitive, and display an increase in fluorescence when released from the acidic vesicular lumen into the extracellular space, called a “FFN Flash.” In Chapter 2, the utility of the dopamine-selective and pH-sensitive functionality of FFN102 to study the mechanisms that regulate changes in pre-synaptic plasticity, a critical component of neurotransmission was explored. This included using the FFN flash to quantitatively trace dopamine release, changes in the release probability of individual release sites, and changes in vesicular loading that can affect quantal size. The second goal of this thesis research, as detailed in Chapters 3 and 4, sought to expand the substrate scope of the FFN program to neurotransmitter systems other than dopamine. Described in Chapter 3, is the identification of a fluorescent phenylpyridinium, APP+, with excellent labeling for dopamine, norepinephrine, and serotonin neurons, however, the properties of the probe were found to be ill-suited for measuring neurotransmitter release. As a result, it was concluded that this class of compounds was not suitable for generating viable FFN leads. In contrast, Chapter 4 highlights the design, synthesis, and screening towards generating the novel noradrenergic-specific FFN, FFN270. This probe was further tested for application in acute murine brain slices where it labeled noradrenergic neurons, and was demonstrated to release upon stimulation. This chapter also describes the application of this compound in a series of in vivo experiments, where the ability to measure norepinephrine release from individual release sites was demonstrated in a living animal for the first time. This work opens the possibility for many exciting future FFN experiments studying the presynaptic regulation of neurotransmission in vivo.

Synapses play a critical role in neural circuits, and their highly specialized structures and biochemical characteristics have been widely studied in learning and memory. Along with their role in signal transmission, synapses also serve as adhesion structures, yet their mechanical characteristics have not received much attention. Given the important role of mechanics in cell adhesion, mechanical studies of synapses could offer insights into synaptic development, maintenance, and function. Here, I investigated synaptic elasticity in cultured rat hippocampal neurons and suggest that mechanical elasticity may be related to synaptic plasticity. I used torsional harmonic atomic force microscopy (TH-AFM) to measure the nanomechanical properties of functional mature excitatory synapses, whose identity and activity was verified by fluorescence microscopy. I combined TH-AFM with transmission electron microscopy and found that high stiffness of synapses originated from postsynaptic spines, not presynaptic boutons. I observed that spines at functional mature excitatory synapses were on average 10 times stiffer than dendritic shafts and that the distribution of spine stiffness exhibited a lognormal-like pattern. Importantly, I found that spine stiffness was correlated with spine size, and it is well established that spine size is correlated with synaptic strength. Based on the stiffness measurements and theoretical modelling of cell adhesion stability, I suggest that stiffness not only helps maintain spine morphology in the presence of synapse adhesion, but also helps stabilize synaptic adhesion. I propose a mechanical synaptic plasticity model. According to this model, mechanical strength leads to functional strength, which could provide a potential causal link between structural plasticity and functional plasticity of synapses.