Fragile X Syndrome (FXS) is the most frequent form of inherited mental retardation, and characterized by an abundance of immature postsynaptic dendritic spines in adult cortical neurons. The objective of this project is to examine spine dynamics and morphology in different cortical regions and layers of the brain during disease progression in a mouse model of FXS (Fmr1 KO), and to explore potential therapeutic strategies targeting different signaling pathways and cell types to correct both synaptic structural and learning behavioral defects. Using transcranial two-photon microscopy, in combination with molecular approaches to manipulate gene expression in individual cortical neurons in vivo, we propose 3 aims.
Aim 1 systematically examines altered dendritic spine morphology and dynamics in the cortex of developing and adult Fmr1 KO mice. It will directly test the current hypothesis that FXS results from a developmental defect in spine pruning and maturation.
Aim 2 correlates the progression of learning disability with the development of spine abnormality. It also dissects and compares the effect of two potential therapeutic strategies for FXS on synaptic structural/function and learning behavior.
Aim 3 investigates neuronal and glial roles in abnormal development of the dendritic spine of cortical neurons in Fmr1 KOs. Results from the proposed studies will provide much needed details about spine dynamism during the pathogenesis of FXS in mice. Such information will help to elucidate the cellular mechanisms for this disease and potentially lead to identification of new cellular targets for treatment.
Fragile X Syndrome (FXS) is the most common inherited cause of mental impairment and the most common known cause of autism. Utilizing in vivo imaging of brain synapses and single cell molecular manipulation, this project investigates cellular mechanisms underlying pathogenesis of FXS. It also examines the rescue of synaptic structure/function, as well as learning behavior, by pharmacological and behavioral treatments of FXS. Therefore, these data may be used to point out new directions for therapies with novel targets or behavioral interventions.
|Martin, P-M; Stanley, R E; Ross, A P et al. (2018) DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/?-catenin signaling. Mol Psychiatry 23:467-475|
|Hodges, Jennifer L; Yu, Xinzhu; Gilmore, Anthony et al. (2017) Astrocytic Contributions to Synaptic and Learning Abnormalities in a Mouse Model of Fragile X Syndrome. Biol Psychiatry 82:139-149|
|Lu, Ju; Zuo, Yi (2017) Clustered structural and functional plasticity of dendritic spines. Brain Res Bull 129:18-22|
|Tjia, Michelle; Yu, Xinzhu; Jammu, Lavpreet S et al. (2017) Pyramidal Neurons in Different Cortical Layers Exhibit Distinct Dynamics and Plasticity of Apical Dendritic Spines. Front Neural Circuits 11:43|
|Yu, Xinzhu; Zuo, Yi (2014) Two-photon in vivo imaging of dendritic spines in the mouse cortex using a thinned-skull preparation. J Vis Exp :|
|Chen, Chia-Chien; Lu, Ju; Zuo, Yi (2014) Spatiotemporal dynamics of dendritic spines in the living brain. Front Neuroanat 8:28|
|Zemmar, Ajmal; Weinmann, Oliver; Kellner, Yves et al. (2014) Neutralization of Nogo-A enhances synaptic plasticity in the rodent motor cortex and improves motor learning in vivo. J Neurosci 34:8685-98|
|Chen, Chia-Chien; Gilmore, Anthony; Zuo, Yi (2014) Study motor skill learning by single-pellet reaching tasks in mice. J Vis Exp :|
|Yu, Xinzhu; Wang, Gordon; Gilmore, Anthony et al. (2013) Accelerated experience-dependent pruning of cortical synapses in ephrin-A2 knockout mice. Neuron 80:64-71|
|Djurisic, Maja; Vidal, George S; Mann, Miriam et al. (2013) PirB regulates a structural substrate for cortical plasticity. Proc Natl Acad Sci U S A 110:20771-6|
Showing the most recent 10 out of 11 publications