When good synapses go bad: dendritic spine dysgenesis in a mouse model of Fragile X mental retardation
type: CreativeWork
description: Fragile X Syndrome (FXS) is the leading inherited cause of mental retardation, and the most common identified genetic cause of autism. Although many phenotypes have been associated with the disorder, arguably the most well-studied and interesting is a pattern of dendritic spine “dysgenesis”, found in patients and animal models of the disorder. Specifically, dendritic spines, thorn-like protrusions associated with synapses, appear “immature”: often exhibiting abnormal length and shape, and found in higher than typical density in many brain regions. The phenotype described is consistent with the hypothesis that deficient synaptic pruning results in the observed spine phenotype. However, directly testing this hypothesis is not possible using traditional methods because the history and fate of particular spines is unknown. Through the use of repeated in vivo imaging using 2-photon microscopy I was able to track the fate of individual spines over different periods of development on layer V dendritic tufts. Spine turnover, including both the formation of new spines and the elimination of existing spines, is enhanced in the Fmr1 knockout (KO) animals compared with wildtype (WT) controls. Furthermore, the increased population of transient spines in the KO mice are not sensitive to modulation by sensory experience, such as by chessboard whisker trimming. Newly formed and eliminated spines were found to be more immature appearing compared to stable spines, suggesting that these spines could contribute to the abnormal spine profile described in Fragile X. However, multiple experiments showed KO spines from the layer V dendritic tufts do not display the spine phenotype previously described for this region of neocortex. Instead, my analysis of spine morphology and dynamics in this region suggests that morphology and size are strong predictors of instability, but that in the KO mouse, there is some dysregulation of this relationship. Using lithium, a model pharmacological treatme…
abstract: Fragile X Syndrome (FXS) is the leading inherited cause of mental retardation, and the most common identified genetic cause of autism. Although many phenotypes have been associated with the disorder, arguably the most well-studied and interesting is a pattern of dendritic spine “dysgenesis”, found in patients and animal models of the disorder. Specifically, dendritic spines, thorn-like protrusions associated with synapses, appear “immature”: often exhibiting abnormal length and shape, and found in higher than typical density in many brain regions. The phenotype described is consistent with the hypothesis that deficient synaptic pruning results in the observed spine phenotype. However, directly testing this hypothesis is not possible using traditional methods because the history and fate of particular spines is unknown. Through the use of repeated in vivo imaging using 2-photon microscopy I was able to track the fate of individual spines over different periods of development on layer V dendritic tufts. Spine turnover, including both the formation of new spines and the elimination of existing spines, is enhanced in the Fmr1 knockout (KO) animals compared with wildtype (WT) controls. Furthermore, the increased population of transient spines in the KO mice are not sensitive to modulation by sensory experience, such as by chessboard whisker trimming. Newly formed and eliminated spines were found to be more immature appearing compared to stable spines, suggesting that these spines could contribute to the abnormal spine profile described in Fragile X. However, multiple experiments showed KO spines from the layer V dendritic tufts do not display the spine phenotype previously described for this region of neocortex. Instead, my analysis of spine morphology and dynamics in this region suggests that morphology and size are strong predictors of instability, but that in the KO mouse, there is some dysregulation of this relationship. Using lithium, a model pharmacological treatme…
author: Aldridge, Georgina
language: en
keywords: Fragile X Syndrome, dendritic spines, development, 2-photon, multiphoton, lithium, Gene Therapy, viral vector, Fragile X Mental Retardation Protein (FMRP), synapse, mouse model
date published: 2012-02-01T00:55:01Z
date modified: 2026-07-22T22:25:27Z
provider: University of Illinois - Urbana-Champaign
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Illinois at Urbana-Champaign

PropertyValue
property ID: Handle
value: http://hdl.handle.net/2142/29550