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Fragile X syndrome (FrX) is the most common inherited form of mental retardation in males with an estimated frequency of 1/4000. It is caused by the absence of the fragile X mental retardation protein (FMRP) encoded by the silenced fragile X mental retardation gene (Fmr1). How the lack of FMRP results in mental retardation and the function of FMRP in the normal brain are subjects of considerable interest.
One approach to these issues is the study of a fragile X knockout (fmr1 KO) mouse, which does not express FMRP and has some of the characteristics of patients with fragile X syndrome, including enlarged testicles, long, thin dendritic spines, some subtle spatial learning abnormalities, auditory hypersensitivity and increased susceptibility to audiogenic seizures. The fmr1 KO, therefore, appears to be a good animal model for the human disorder and permits an assessment of the effect of the Fmr1 mutation on a constant genetic background. Our behavioral studies [1] showed that fmr1 KO mice exhibit hyperactivity and a higher rate of entrance into the center of an open field compared with controls, suggesting decreased levels of anxiety. Their performance on a passive avoidance task was impaired, which |
| suggested a deficit in learning and memory. In an effort to understand what brain regions are involved in the behavioral abnormalities, we measured regional cerebral metabolic rates for glucose (rCMRglc) in 38 regions in adult male fmr1 KO and wild-type (WT) littermates with the quantitative autoradiographic [14C]deoxyglucose method. We found rCMRglc was higher in all 38 regions in fmr1 KO mice, and in 26 of the regions differences were statistically significant [1]. Differences in rCMRglc ranged from 12% to 46%, and the greatest differences occurred in regions of the limbic system and primary sensory and posterior parietal cortical areas. Regions most affected were consistent with behavioral deficiencies and regions in which FMRP expression is highest. Higher rCMRglc in fragile X mice may also be a reflection of abnormalities found in dendritic spines. |  Digitized [14C]deoxyglucose autoradiograms (B,D,F,H) and corresponding Nissl-stained sections (A,C,E,G) from WT (A-D) and fmr1 KO (E-H) mice. [1] |
| FMRP is an RNA-binding protein that has been shown to suppress translation of certain mRNAs in vitro. We applied the quantitative autoradiographic L-[1-C14]leucine method [2] to the in vivo determination of rates of cerebral protein synthesis (rCPS) in adult WT and fmr1 KO mice [3]. Our results demonstrate a regionally selective elevation in rCPS in fmr1 KO mice and support the hypothesis that FMRP is a suppressor of translation in brain in vivo. Dysregulation of protein synthesis is very likely close to the underlying etiology of symptoms of FrX. Measurement of rCPS in patients with FrX syndrome may provide a means of measuring the progress of the disease and efficacy of treatments. With the development of the |  Digitized [C14]leucine autoradiograms from 6-month old WT (B) and fmr1 KO (C) mice. Images have been color-coded for rCPS. For comparison with the distribution of FMRP in a WT mouse brain, we used immunohistochemistry for FMRP. Immunostaining of FMRP in the CA1 sector of the pyramidal cell layer is shown in D. The CA1, CA2, and CA3 sectors of the pyramidal cell layer can be located in a thionin-stained section from a WT mouse (A). [3] |
| L-[1-C11]leucine method for measurement of rCPS in human subjects with positron emission tomography [4, 5], we can now test this possibility in FrX patients. These studies are now being planned in collaboration with the NIH PET Department. |
This work is supported, in part, by the Fragile X Research Foundation.
References:
[1] Qin M, Kang J, Smith CB. Increased rates of cerebral glucose metabolism in a mouse model of fragile X mental retardation. Proc Natl Acad Sci USA 2002, 99:15758-15763 [pdf]. (return to text)
[2] Smith CB, Deibler GE, Eng N, Schmidt K, Sokoloff L. Measurement of local cerebral protein synthesis in vivo: Influence of recycling of amino acids derived from protein degradation. Proc Natl Acad Sci USA 1988, 85:9341-9345 [pdf]. (return to text)
[3] Qin M, Kang J, Burlin TV, Jiang C, Smith CB. Postadolescent changes in regional cerebral protein synthesis: an in vivo study in the Fmr1 null mouse. J Neuroscience 2005, 25(20):5087-5095 [pdf]. (return to text)
[4] Schmidt KC, Cook MP, Qin M, Kang J, Burlin TV, Smith CB. Measurement of regional rates of cerebral protein synthesis with L-[1-C11]leucine and PET with correction for recycling of tissue amino acids: I. Kinetic modeling approach. J Cereb Blood Flow Metab 2005, 25:617-628 [pdf]. (return to text)
[5] Smith CB, Schmidt KC, Qin M, Burlin TV, Cook MP, Kang J, Saunders RC, Bacher JD, Carson RE, Channing MA, Eckelman WC, Herscovitch P, Laverman P, Vuong B-K. Measurement of regional rates of cerebral protein synthesis with L-[1C11]leucine and PET with correction for recycling of tissue amino acids: II. Validation in rhesus monkeys. J Cereb Blood Flow Metab 2005, 25:629-640 [pdf]. (return to text)
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