UC Riverside

Fragile X syndrome (FXS) is the most common single-gene inherited form of intellectual disability, with behaviors characteristic of autism. FXS is caused by silencing of the Fragile X mental retardation gene (FMR1). Individuals with FXS display childhood seizures, hyperactivity, anxiety, developmental delay, attention deficits, and visual-spatial memory impairment, as well as repetitive and perseverative behavior. Many of these behavioral deficits are also associated with mice that lack the Fmr1 gene (Fmr1^-/-). Furthermore, Fmr1^-/- neurons, similar to the human condition, exhibit defects in dendritic spine maturation which may underlie the cognitive and behavioral abnormalities in FXS. Dendritic spines are small protrusions on the surface of the dendrite that receive the majority of excitatory synapses in the brain and changes in their morphology affect synaptic efficacy. Much research has focused on treatment options to improve the deficits associated with FXS to ultimately improve the quality of life for the individuals afflicted with this syndrome. The basis of my research examined how minocycline improved behavioral deficits, such as a reduction in hyperactivity, anxiety, obsessive compulsive tendencies and susceptibility to audiogenic seizures as well as promoted dendritic spine maturation in the Fmr1^-/-. Minocycline is a semi-synthetic antibiotic that also has many non-microbial targets, such as inhibiting the enzyme matrix metalloproteinase-9 (MMP-9). MMP-9 has been implicated in many neurological disorders, including multiple sclerosis, cerebral ischemia and mild cognitive impairment. The concurrent focus of my project was on the involvement of MMP-9 in FXS. We discovered that active MMP-9 promoted an immature dendritic spine profile in cultured hippocampal neurons, and that MMP-9 expression and activity were upregulated within the hippocampus of the Fmr1^-/-. To further expound upon the role of MMP-9, we also analyzed MMP-9's expression levels within the blood and brain of individuals with FXS and found a decrease in relative activity in the blood, but an increase in total expression within postmortem hippocampal and neocortical tissue. Overall, this study elucidated a novel mechanism for MMP-9 that appears to play a causative role in the pathology of FXS as well as provided a new therapeutic option for FXS treatment.