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http://hdl.handle.net/11375/20479
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DC Field | Value | Language |
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dc.contributor.advisor | Doering, Laurie C. | - |
dc.contributor.author | Cheng, Connie | - |
dc.date.accessioned | 2016-09-23T19:35:50Z | - |
dc.date.available | 2016-09-23T19:35:50Z | - |
dc.date.issued | 2016 | - |
dc.identifier.uri | http://hdl.handle.net/11375/20479 | - |
dc.description.abstract | Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and autism spectrum disorders. The disorder is typically caused by decreased or absent levels of the fragile X mental retardation protein (FMRP) due to a loss-of-function mutation in the fragile X mental retardation 1 (FMR1) gene. Astrocytes are key participants in various aspects of brain development and function, many of which are executed via secreted proteins. Specifically, the astrocyte-secreted matricellular protein thrombospondin-1 (TSP-1) has been highly implicated in the regulation of neuronal synaptogenesis. Previously, we have shown that astrocytes can prevent the abnormal dendrite morphology and dysregulated synapses that characterize FXS. While we have identified that astrocytes affect synapse development in vitro, the role of secreted factors has not been elucidated. Utilizing a Fragile X mouse model and a neuron-astrocyte, non-contact co-culture system, we investigated the contributions of soluble TSP-1 in spine and synapse development. We found that TSP-1 protein levels were reduced in Fmr1 knockout (KO) cultured astrocytes and astrocyte-conditioned media (ACM). TSP-1 levels were also downregulated in the cortex and hippocampus of Fragile X mice in contrast to their wildtype (WT) counterparts. Additionally, Fmr1 KO hippocampal neurons exhibited significant deficits in dendritic spine morphology and excitatory synapse formation following long-term culture. However, all spine and synaptic abnormalities were prevented in the presence of either ACM or a feeder layer derived from WT astrocytes, or following the application of exogenous TSP-1, thereby suggesting a role for soluble glial factors in the formation and maturation of spines and synapses. These findings presented here provide strong evidence for astroglia-derived TSP-1 as a strong promoter of neuronal development in FXS. Therefore, defects in astrocyte function and secreted molecules during early development may contribute to the abnormal neurobiology in FXS. | en_US |
dc.language.iso | en | en_US |
dc.title | The Role of Astrocyte-Secreted Thrombospondin-1 in the Fragile X Mouse Model | en_US |
dc.type | Thesis | en_US |
dc.contributor.department | Neuroscience | en_US |
dc.description.degreetype | Dissertation | en_US |
dc.description.degree | Doctor of Philosophy (PhD) | en_US |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Cheng_Connie_FinalSubmission2016August_PhD.pdf | PhD Dissertation | 16.63 MB | Adobe PDF | View/Open |
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