Fragile X-syndrome is caused by functional inactivation ofthe Fmri gene, and represents the most common genetic form of intellectual disability. However, the mechanisms of fragile X-syndrome pathogenesis are incompletely understood. As a result, few potential therapeutic avenues to treat the disorder are available. Based on observations that different forms of synaptic plasticity, most prominently mGluR5-dependent LTD and retinoic acid-dependent homeostatic plasticity, are blocked in Fmri knockout mice, the present project is led by the overall hypothesis that fragile X-syndrome involves an impairment of experience-driven synaptic excitation/inhibition (E/l) adjustments. Guided by this hypothesis, we propose four specific aims that explore the nature and developmental dynamics of FXS pathogenesis in mouse models using conditional and constitutive Fmri gene inactivation and a combination of biochemical, physiological, and behavioral assays, with a focus on activity- and experience-induced changes in the synaptic excitatory/inhibitory (E/l) state. Additionally, we propose to investigate whether activating oxytocin signaling can restore aspects ofthe altered E/l state in the hippocampal circuitry of FXS mice. With these experiments, we aim to establish in a mouse model how synaptic dysfunction, especially that related to synaptic E/l imbalance, is linked to the behavioral defects in FXS, and to obtain a comprehensive understanding ofthe development of FXS-related pathology. These studies will lead to a better and more comprehensive understanding of fragile X-syndrome and define disease mechanisms that could lead to the identification of potential therapeutic targets.

Public Health Relevance

Studying the basic pathophysiology of fragile X-syndrome in a mouse model and examining its developmental dynamics will provide insight into fundamental questions relevant to treating this disorder. We will explore the influence of activity and behavioral history on subsequent synaptic E/l state and learning capacity to see if activating oxytocin signaling restores the synaptic E/l state to a normal level to support normal learning.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD084215-01
Application #
8921625
Study Section
Special Emphasis Panel (ZHD1-DSR-Y (53))
Program Officer
Urv, Tiina K
Project Start
2014-09-22
Project End
2019-05-31
Budget Start
2014-09-22
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$589,286
Indirect Cost
$177,987
Name
Stanford University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Arendt, Kristin L; Zhang, Yingsha; Jurado, Sandra et al. (2015) Retinoic Acid and LTP Recruit Postsynaptic AMPA Receptors Using Distinct SNARE-Dependent Mechanisms. Neuron 86:442-56