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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH094449-03
Application #
8644928
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Panchision, David M
Project Start
2012-04-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
$370,221
Indirect Cost
$120,221
Name
University of California Santa Cruz
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
125084723
City
Santa Cruz
State
CA
Country
United States
Zip Code
95064
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