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Identification of a Role for Huntingtin in the Control of Synaptic Connectivity in Circuits Disrupted by Huntington’s DiseaseMcKinstry, Spencer Unruh January 2015 (has links)
<p>Huntington’s disease (HD) is an adult-onset, neurodegenerative disease caused by an autosomal dominant mutation in the huntingtin (HTT) gene. HD patients suffer from motor, cognitive, and psychiatric symptoms. The pathogenic mutation of HD is expansion of a CAG repeat in the first exon of the HTT that encodes for a polyglutamine (poly-Q) repeat in the huntingtin protein (Htt). HD results in neurodegeneration of the striatum and cortex, which is thought to underlie the development of HD symptoms, but recent evidence has shown that there are alterations to the connectivity of patients’ brains preceding degeneration. This study focuses on how wild type Htt contributes to establishing and maintaining synaptic connectivity and how a loss of normal Htt function may contribute to the synaptic alterations in HD.</p><p>In this study, I examined the role of wild type Htt in synapse formation and maturation synapses in the basal ganglia circuit, and I examined how loss of wild type Htt function may affect the pathogenesis of HD. To do so, I created conditional deletions of Htt in the mouse brain by crossing a floxed allele of Huntingtin to transgenic Cre lines. I conditionally deleted Htt from the cortex and the indirect pathway spiny neurons (iSPNs) of the striatum using Emx1-Cre and Adora2A-Cre, respectively. I also used a knock-in mouse model of HD, the zQ175 mouse, to examine alterations caused by the HD mutation. I used imaging and electrophysiological techniques to determine how loss of Huntingtin affected synapse number, function, and morphology in the cortex, striatum, and basal ganglia. </p><p>In the cortex and striatum, loss of Htt leads to disruptions in synaptic connectivity followed by neuronal stress and death. Htt is critical for moderating the formation of excitatory synapse formation in both the cortex and striatum, and that in the cortex this function is lost in HD. In the striatum, Htt is required for stabilizing striatopallidal synapses, and for proper basal ganglia function. </p><p>In order to explore the molecular mechanisms behind Htt’s control of excitatory synapse formation, I investigated its interaction with α2δ-1. α2δ-1 is a genetic modifier of mutant Htt toxicity that our lab had previously identified as the neuronal receptor of the synaptogenic Thrombospondin family (TSP) of proteins. I used in vitro neuronal cultures and biochemical analysis to determine how Htt interacts with α2δ-1 and how Htt affects TSP/α2δ-1 excitatory synapse formation. I characterized α2δ-1’s biochemical interaction with Htt and discovered that Htt postsynaptically suppresses excitatory synapses.</p><p>Taken together, these results suggest that wild type Htt functions to moderate excitatory activity in the brain. It slows the formation of excitatory connections and stabilized inhibitory ones, which may protect the brain from excitotoxic damage. These results show that Htt plays an important role in maintaining neuronal health and the establishment of synaptic connectivity in cortical and striatal circuits.</p> / Dissertation
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Molecular Mechanisms of Laminar Circuit Formation in Visual CortexTomorsky, Johanna 30 April 2019 (has links)
The mammalian visual system develops to perform many complex tasks that allow us to perceive the natural world. These tasks rely on a dense network of synaptic connections transporting visual information both to and within visual cortex (V1). The laminar organization and functional properties of visual cortical neurons are largely conserved across mammals, and the mouse has been adopted as a model organism to study the development of this cortical circuit. Neurons in each cortical layer must find the correct synaptic partners for the optimal receipt, transfer, and processing of information. The molecular cues guiding the development of these connections, however, are largely unknown.
In this thesis, I identify and then examine the role of molecular factors important for synapse formation in layer 2/3 (L2/3) of visual cortex. L2/3 neurons are highly interconnected and fire selectively to a refined set of visual stimuli. The developmental refinement of these visual preferences has been shown to occur in the week following eye opening, corresponding with a period of intense synapse formation and dynamic gene expression in mouse V1. In Chapters II–IV, I use the TU-tagging technique to identify molecular factors enriched L2/3 neurons before and after eye opening and identify several candidate genes with potential functions in synapse formation.
In Chapter V, I examine the function of cell adhesion molecules nectin-1 and nectin-3, identified here as enriched in L2/3 visual cortex at eye opening, and previously shown to interact across synaptic junctions. I focus mainly on the effect of nectin-3 (having post-synaptic localization in hippocampus) on post-synaptic dendritic spine densities in developing L2/3 cortical neurons. I show that nectin-3 knockdown further increases spine densities after eye opening, while overexpressing a full length or truncated nectin-3 protein reduces spine densities. I conclude that nectin-3 may have a role in synapse formation following eye opening, and propose a mechanism describing the effects observed. Here, I describe a unique approach for understanding how cell-type specific connections are formed in visual cortex, beginning with the spatiotemporal examination gene expression and followed by the spatiotemporal manipulation of a single gene.
This dissertation includes previously published co-authored material.
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The role of gamma-protocadherins in interneuron survival and circuit formation in the developing spinal cordPrasad, Tuhina 01 December 2009 (has links)
Protocadherins (Pcdhs) are a large family of adhesion molecules which have structure similar to that of classical cadherins. About 60 Pcdh genes are organized into three clusters (-á,- â and- ã), which are arranged contiguously on a single chromosome in mammals. Mice in which the 22-gene Pcdh- ã locus has been deleted die within a few hours of birth and show defects in movement and reflexes, extensive neurodegeneration in the spinal cord, and loss of synapses. Further studies have shown that loss of ã-Pcdhs has a primary effect on the formation or maintenance of synapses that can be dissociated from its role in cell survival. Extensive apoptotic cell death observed during the late embryonic development period in the spinal cord of the Pcdh- ã del/del mutant mice is confined to molecularly distinct populations of spinal interneurons. Analysis of cell death patterns during development of spinal cords from wild-type, the Pcdh- ã del/del and Bax -/- mice in which cell death is blocked due to deletion of a proapoptotic protein, confirmed that loss of ã-Pcdhs exacerbates a previously undocumented normal developmental pattern of spinal interneuron apoptosis. Restricted disruption of the Pcdh- ã gene cluster within specific neuronal populations suggested that ã-Pcdhs can control neuronal survival in a non-cell autonomous manner. Loss of ã-Pcdhs also resulted in an aberrant pattern of 1a proprioceptive sensory afferent (1aPSA) terminals in the spinal cord. In Pcdh- ã del/del mice the area occupied by 1aPSA terminals per motor neuron increased by 150% over the control with a corresponding reduction of 30% in the area occupied by 1aPSA terminals on the ventral interneurons. Further analysis in the Pcdh- ã del/del; Bax-/- double mutants, as well as in mouse lines in which Pcdh- ã gene cluster disruption was confined to specific neuronal subpopulations, suggested that this aberrant pattern was a result of both the increased loss of ventral interneurons in mutants, as well as a cell autonomous requirement of ã-Pcdhs in the 1aPSA and their intermediate target ventral interneurons. These studies provide evidence that the ã-Pcdhs mediate homophilic interactions that are important for the formation of multiple neuronal circuits, and are critical molecules in the regulation of interneuron survival and CNS development.
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Examining Dynamic Aspects of Presynaptic Terminal Formation via Live Confocal MicroscopyBury, Luke Andrew Dascenzo 03 September 2015 (has links)
No description available.
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Roles of α-neurexins in synapse stabilization and Ca<sup>2+</sup>-dependent endocrine secretion / Die Rolle von α-Neurexinen bei der Stabilisierung von Synapsen und bei Ca<sup>2+</sup>-abhängiger endokriner SekretionDudanova, Irina 17 April 2007 (has links)
No description available.
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