Sensory hypersensitivities are common, clinically distressing features of Fragile X Syndrome (FXS). Preclinical evidence suggests this abnormality may result from synaptic hyper-excitability in sensory systems. This model predicts reduced sensory habituation to repeated stimulus presentation. Fourteen adolescents and adults with FXS and 15 age-matched controls participated in a modified auditory gating task using trains of 4 identical tones during dense array electroencephalography (EEG). Event-related potential and single trial time–frequency analyses revealed decreased habituation of the N1 event-related potential response in FXS, and increased gamma power coupled with decreases in gamma phase-locking during the early-stimulus registration period. EEG abnormalities in FXS were associated with parent reports of heightened sensory sensitivities and social communication deficits. Reduced habituation and altered gamma power and phase-locking to auditory cues demonstrated here in FXS patients parallels preclinical findings with Fmr1 KO mice. Thus, the EEG abnormalities seen in FXS patients support the model of neocortical hyper-excitability in FXS, and may provide useful translational biomarkers for evaluating novel treatment strategies targeting its neural substrate.

We have generated mice with markedly elevated plasma levels of human low density lipoprotein (LDL) and reduced plasma levels of high density lipoprotein. ). The mice were killed at 6 mo, and the percent area of the aortic intimal surface that stained positive for neutral lipid was quantified. Mean percent areas of lipid staining were not significantly different between the LDLR ؊͞؊ and LDLR ؊͞؊ ;Tg(apoa ؉͞؊ ) mice (1.0 ؎ 0.2% vs. 1.4 ؎ 0.3%). However, the LDLR ؊͞؊ ;Tg(apoB ؉͞؉ ) mice had Ϸ15-fold greater mean lesion area than the LDLR ؊͞؊ mice. No significant difference was found in percent lesion area in the LDLR ؊͞؊ ;Tg(apoB ؉͞؉ ) mice whether or not they expressed apo(a) [18.5 ؎ 2.5%, without lipoprotein(a), Lp(a), vs. 16.0 ؎ 1.7%, with Lp(a)]. Histochemical analyses of the sections from the proximal aorta of LDLR ؊͞؊ ;Tg(apoB ؉͞؉ ) mice revealed large, complex, lipid-laden atherosclerotic lesions that stained intensely with human apoB-100 antibodies. In mice expressing Lp(a), large amounts of apo(a) protein colocalized with apoB-100 in the lesions. We conclude that LDLR ؊͞؊ ; Tg(apoB ؉͞؉ ) mice exhibit accelerated atherosclerosis on a chow diet and thus provide an excellent animal model in which to study atherosclerosis. We found no evidence that apo(a) increased atherosclerosis in this animal model.Atherosclerosis is a complex, multifactorial process whose analysis has been greatly facilitated by the development of genetically modified mice. ApoE-deficient mice (apoE Ϫ͞Ϫ ) are currently the most widely utilized animal model for the study of atherosclerosis (1, 2). ApoE Ϫ͞Ϫ mice maintained on a low fat, mouse-chow diet have dramatically elevated plasma levels of cholesterol, and they develop extensive atherosclerotic lesions widely distributed throughout the aorta (1-5). The effect of other genes on the development of atherosclerosis has been examined by crossing the apoE Ϫ͞Ϫ mice with other genetically manipulated animals (6-8).In wild-type mice, Ϸ90% of plasma cholesterol circulates in high density lipoproteins (HDL). In ApoE Ϫ͞Ϫ mice, the cholesterol is predominantly in the very low density lipoproteins (VLDL) and in the intermediate density lipoprotein fractions (IDL) (1, 2). The most common lipoprotein pattern in humans with coronary artery disease consists of elevated plasma levels of low density lipoprotein cholesterol (LDL-C) and decreased HDL-C, with or without increases in plasma IDL and VLDL. The strong association between plasma LDL-C and coronary artery disease in humans is reflected in the clinical outcome of subjects with familial hypercholesterolemia (9). Familial hypercholesterolemia is an autosomal dominant disorder caused by mutations in the LDL receptor (LDLR) gene, which encodes a cell surface receptor that binds and internalizes plasma LDL. Individuals heterozygous for a mutation at the LDLR locus have 2-to 3-fold elevated levels of LDL-C and a striking increase in the incidence of premature coronary artery disease (9). Familial hypercholesterolemia homozygotes [LDLR Ϫ͞Ϫ ] have ...

Mouse embryonic stem (ES) cells are endowed with four unusual properties. They are exceedingly small, exhibiting an intracellular volume two to three orders of magnitude smaller than that of normal mammalian cells. Their rate of cell division, wherein cell doubling takes place in only 4-5 h, is more rapid than even the fastest growing cancer cell lines. They do not senesce. Finally, mouse ES cells retain pluripotency adequate to give rise to all cell types present in either gender of adult mice. We have investigated whether some or all of these unusual features might relate to the possibility that mouse ES cells exist in a specialized metabolic state. By evaluating the abundance of common metabolites as a function of the conversion of mouse ES cells into differentiated embryoid bodies, it was observed that the most radical changes in metabolite abundance related to cellular building blocks associated with one carbon metabolism. These observations led to the discovery that mouse ES cells use the threonine dehydrogenase (TDH) enzyme to convert threonine into acetyl-coenzyme A and glycine, thereby facilitating consumption of threonine as a metabolic fuel. Here we describe the results of a combination of nutritional and pharmacological studies, providing evidence that mouse ES cells are critically dependent on both threonine and the TDH enzyme for growth and viability.

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