Carolyn Beebe Smith

In humans, failure to express the fragile X mental retardation protein (FMRP) gives rise to fragile X syndrome, the most common form of inherited mental retardation. A fragile X knockout ( fmr1 KO) mouse has been described that has some of the characteristics of patients with fragile X syndrome, including immature dendritic spines and subtle behavioral deficits. In our behavioral studies, fmr1 KO mice exhibited hyperactivity and a higher rate of entrance into the center of an open field compared with controls, suggesting decreased levels of anxiety. Our finding of impaired performance of fmr1 KO mice on a passive avoidance task is suggestive of a deficit in learning and memory. In an effort to understand what brain regions are involved in the behavioral abnormalities, we applied the [ ¹⁴ C]deoxyglucose method for the determination of cerebral metabolic rates for glucose (CMR _glc ). We measured CMR _glc in 38 regions in adult male fmr1 KO and WT littermates. We found CMR _glc was higher in all 38 regions in fmr1 KO mice, and in 26 of the regions, differences were statistically significant. Differences in CMR _glc 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 are consistent with behavioral deficiencies and regions in which FMRP expression is highest. Higher CMR _glc in fragile X mice may be a function of abnormalities found in dendritic spines.

Local rates of cerebral protein synthesis (lCPS _leu ) were measured with the quantitative autoradiographic [1- ¹⁴ C]leucine method in a genetic mouse model ( Pah ^enu2 ) of phenylketonuria. As in the human disease, Pah ^enu2 mice have a mutation in the gene for phenylalanine hydroxylase. We compared adult homozygous (HMZ) and heterozygous (HTZ) Pah ^enu2 mice with the background strain (BTBR). Arterial plasma concentrations of phenylalanine (Phe) were elevated in both HMZ and HTZ mutants by 21 times and 38%, respectively. In the total acid-soluble pool in brain concentrations of Phe were higher and other neutral amino acids lower in HMZ mice compared with either HTZ or BTBR mice indicating a partial saturation of the l -amino acid carrier at the blood brain barrier by the elevated plasma Phe concentrations. In a series of steady-state experiments, the contribution of leucine from the arterial plasma to the tRNA-bound pool in brain was found to be statistically significantly reduced in HMZ mice compared with the other groups, indicating that a greater fraction of leucine in the precursor pool for protein synthesis is derived from protein degradation. We found reductions in lCPS _leu of about 20% throughout the brain in the HMZ mice compared with the other two groups, but no reductions in brain concentrations of tRNA-bound neutral amino acids. Our results in the mouse model suggest that in untreated phenylketonuria in adults, the partial saturation of the l -amino acid transporter at the blood–brain barrier may not underlie a reduction in cerebral protein synthesis.