Dysregulation of Protein Synthesis in Fragile X Syndrome

在2012年资助期内，我们完成了以下工作：

During the 2012 funding period, we addressed the following: We measured rCPS in 15 male subjects (18-24 y) with the full fragile X mutation and 12 age-matched healthy volunteers. Because of their impairments it was necessary to study FXS subjects under deep sedation. We used propofol as the sedating agent. Each healthy volunteer was studied twice, once awake and once under propofol-sedation, and we found no differences in rCPS in whole brain or in any of the 10 regions examined. Contrary to our hypothesis, FXS subjects under propofol-sedation had statistically significantly reduced rCPS in whole brain, cerebellum, frontal and parietal cortex compared with sedated controls. We considered the possibility that propofol could have a disparate effect on rCPS in FXS subjects thereby masking a baseline elevation in rCPS, and we examined this possibility in the Fmr1 KO mouse model. Our study in adult Fmr1 KO mice showed that propofol results in widespread and significantly decreased rCPS throughout the brain whereas effects in WT mice were very circumscribed and smaller in magnitude. Our observation that treatment with a drug that alters neuronal and possibly synaptic activity also alters rCPS in Fmr1 KO mice has implications for the development of therapeutic strategies for FXS. A manuscript reporting these results is under review. We studied WT and Fmr1 KO mice untreated or treated with lithium-containing chow commenced at weaning and maintained throughout the experiment. Between 8 and 12 weeks of age, mice were subjected to the following behavioral tests: open field, social interaction, elevated plus maze, elevated zero maze and passive avoidance. At 13 weeks, brains were prepared for Golgi staining and analysis of dendritic spine morphology in medial prefrontal cortex. In separate groups of mice treated identically we measured rCPS at 12 weeks of age. We found that compared with untreated WT, untreated Fmr1 KO mice were hyperactive and had reduced anxiety, impaired social interactions, and deficits on the passive avoidance test. Dendritic spines in medial prefrontal cortex were longer and increased in number in Fmr1 KO mice. Lithium treatment ameliorated the hyperactivity and reversed impaired social interaction and learning deficits. Lithium treatment also normalized general anxiety levels and dendritic spine morphology. Moreover, chronic treatment with lithium reversed the increased rCPS found in Fmr1 KO mice and had little, if any, effect on rCPS in WT mice. Increased rCPS in the untreated Fmr1 KO mice compared with WT were found primarily in the limbic system and hypothalamus, whereas the effects of lithium occurred throughout the brain. We extended our studies to examine in hippocampus the effects of lithium treatment on some of the signaling pathways that influence translation. Our results indicate that neither effects on the PI3K/Akt nor the ERK 1/2 pathway can fully account for the effects on rCPS under the basal conditions of our study. Results of these studies were published in International Journal of Neuropsychopharmacology (Liu et al., 2011) and Neurobiology of Disease (Liu et al., 2012).