| Fragile X syndrome (FXS) is the most commonly inherited form of intellectual disability resulting from silencing of FMR1 gene and consequential absence of fragile X mental retardation protein. FXS is commonly studied in Fmr1 KO mouse, which displays similar behavioral and neurological deficits as FXS patients. Many studies have investigated immature Fmr1 KO brain, but little is known about alterations in brain maturation processes, including developmental changes in metabolites, white and gray matter morphology and brain network function. Alterations in metabolites from 1H-magnetic resonance spectroscopy between Fmr1 KO and WT mice revealed included myo-inositol at postnatal-day 30 (PND 30), and taurine at PND 18, 21, and 30. Next, developmental alterations in myelin and white matter were examined in fixed Fmr1 KO mouse brains compared to WT at PND 18, 21, 30 and 60 with histological staining of myelin and MRI techniques to measure volume and magnetization transfer ratio, which is sensitive to myelin proteins and lipids. Fmr1 KO mice revealed decreased myelin density and MTR at PND 18, increased at PND 30 and decreased at PND 60, suggesting altered pattern of myelin formation in Fmr1 KO mouse. Diffusion tensor imaging was used to study microstructural properties of white matter to provide insight into myelin and axon properties in fixed Fmr1 KO brains at PND 18, 21, 30 and 60. Decreased mean, axial and radial diffusivity was found at PND 21 and 30 in Fmr1 KO brains, suggesting alterations in myelin compaction and axonal organization. Finally, alterations in functional connectivity in Fmr1 KO mouse were studied using resting-state functional-MRI. The longitudinal results showed decreased functional connectivity in the auditory and somatomotor networks in Fmr1 KO brain compared to WT at PND 30 and not different by PND 60, suggesting a delay in development of the resting state networks in Fmr1 KO mice. The work in this thesis characterized metabolic, structural, and functional alterations in developing Fmr1 KO mouse brain. |
