scholarly journals Altered Cerebral Protein Synthesis in Fragile X Syndrome: Studies in Human Subjects and Knockout Mice

2013 ◽  
Vol 33 (4) ◽  
pp. 499-507 ◽  
Author(s):  
Mei Qin ◽  
Kathleen C Schmidt ◽  
Alan J Zametkin ◽  
Shrinivas Bishu ◽  
Lisa M Horowitz ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Human Subjects ◽  
Brain Regions ◽  
Synaptic Activity ◽  
Whole Brain ◽  
Propofol Sedation ◽  
Positron Emission ◽  
Cerebral Protein Synthesis

Dysregulated protein synthesis is thought to be a core phenotype of fragile X syndrome (FXS). In a mouse model ( Fmr1 knockout (KO)) of FXS, rates of cerebral protein synthesis (rCPS) are increased in selective brain regions. We hypothesized that rCPS are also increased in FXS subjects. We measured rCPS with the L-[1-11C]leucine positron emission tomography (PET) method in whole brain and 10 regions in 15 FXS subjects who, because of their impairments, were studied under deep sedation with propofol. We compared results with those of 12 age-matched controls studied both awake and sedated. In controls, we found no differences in rCPS between awake and propofol sedation. Contrary to our hypothesis, FXS subjects under propofol sedation had reduced rCPS in whole brain, cerebellum, and cortex compared with sedated controls. To investigate whether propofol could have a disparate effect in FXS subjects masking usually elevated rCPS, we measured rCPS in C57Bl/6 wild-type (WT) and KO mice awake or under propofol sedation. Propofol decreased rCPS substantially in most regions examined in KO mice, but in WT mice caused few discrete changes. Propofol acts by decreasing neuronal activity either directly or by increasing inhibitory synaptic activity. Our results suggest that changes in synaptic signaling can correct increased rCPS in FXS.

scholarly journals Regional Rates of Cerebral Protein Synthesis Measured with l-[1-11C]Leucine and PET in Conscious, Young Adult Men: Normal Values, Variability, and Reproducibility

2008 ◽  
Vol 28 (8) ◽  
pp. 1502-1513 ◽  
Author(s):  
Shrinivas Bishu ◽  
Kathleen C Schmidt ◽  
Thomas Burlin ◽  
Michael Channing ◽  
Shielah Conant ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
White Matter ◽  
Human Subjects ◽  
Intersubject Variability ◽  
Precursor Pool ◽  
Arterial Blood ◽  
Positron Emission ◽  
Mean Differences ◽  
Cortical Regions ◽  
Cerebral Protein Synthesis

We report regional rates of cerebral protein synthesis (rCPS) measured with the fully quantitative l-[1-11C]leucine positron emission tomography (PET) method. The method accounts for the fraction (Λ) of unlabeled amino acids in the precursor pool for protein synthesis derived from arterial plasma; the remainder (1-Λ) comes from tissue proteolysis. We determined rCPS and Λ in 18 regions and whole brain in 10 healthy men (21 to 24 years). Subjects underwent two 90-min dynamic PET studies with arterial blood sampling at least 2 weeks apart. Rates of cerebral protein synthesis varied regionally and ranged from 0.97 ± 0.70 to 2.25 ± 0.20 nmol/g per min. Values of rCPS were in good agreement between the two PET studies. Mean differences in rCPS between studies ranged from 9% in cortical regions to 15% in white matter. The Λ value was comparatively more uniform across regions, ranging from 0.63 ± 0.03 to 0.79 ± 0.02. Mean differences in Λ between studies were 2% to 8%. Intersubject variability in rCPS was on average 6% in cortical areas, 9% in subcortical regions, and 12% in white matter; intersubject variability in Λ was 2% to 8%. Our data indicate that in human subjects low variance and highly reproducible measures of rCPS can be made with the l-[1-11C]leucine PET method.

scholarly journals Reduced Expression of Cerebral Metabotropic Glutamate Receptor Subtype 5 in Men with Fragile X Syndrome

2020 ◽  
Vol 10 (12) ◽  
pp. 899
Author(s):  
James R. Brašić ◽  
Ayon Nandi ◽  
David S. Russell ◽  
Danna Jennings ◽  
Olivier Barret ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Fragile X ◽  
Brain Regions ◽  
Receptor Expression ◽  
Receptor Subtype ◽  
Metabotropic Glutamate ◽  
Positron Emission ◽  
Subcortical Regions

Glutamatergic receptor expression is mostly unknown in adults with fragile X syndrome (FXS). Favorable behavioral effects of negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5) in fmr1 knockout (KO) mouse models have not been confirmed in humans with FXS. Measurement of cerebral mGluR5 expression in humans with FXS exposed to NAMs might help in that effort. We used positron emission tomography (PET) to measure the mGluR5 density as a proxy of mGluR5 expression in cortical and subcortical brain regions to confirm target engagement of NAMs for mGluR5s. The density and the distribution of mGluR5 were measured in two independent samples of men with FXS (N = 9) and typical development (TD) (N = 8). We showed the feasibility of this complex study including MRI and PET, meaning that this challenging protocol can be accomplished in men with FXS with an adequate preparation. Analysis of variance of estimated mGluR5 expression showed that mGluR5 expression was significantly reduced in cortical and subcortical regions of men with FXS in contrast to age-matched men with TD.

scholarly journals Reproducibility of Cerebral Glucose Metabolic Measurements in Resting Human Subjects

1988 ◽  
Vol 8 (4) ◽  
pp. 502-512 ◽  
Author(s):  
Elsa J. Bartlett ◽  
Jonathan D. Brodie ◽  
Alfred P. Wolf ◽  
David R. Christman ◽  
Eugene Laska ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Brain Metabolism ◽  
Human Subjects ◽  
Normal Subjects ◽  
Time Of Day ◽  
Cerebral Glucose Metabolism ◽  
Whole Brain ◽  
Positron Emission ◽  
Subcortical Regions ◽  
Regional Cerebral Glucose Metabolism

Positron emission tomography with 11C-2-deoxyglucose was used to determine the test-retest variability of regional cerebral glucose metabolism in 22 young normal right-handed men scanned twice in a 24-h period under baseline (resting) conditions. To assess the effects of scan order and time of day on variability, 12 subjects were scanned in the morning and afternoon of the same day (a.m.-p.m.) and 10 in the reverse order (p.m.-a.m.) with a night in between. The effect of anxiety on metabolism was also assessed. Seventy-three percent of the total subject group showed changes in whole brain metabolism from the first to the second measurement of 10% or less, with comparable changes in various cortical and subcortical regions. When a scaling factor was used to equate the whole brain metabolism in the two scans for each individual, the resulting average regional changes for each group were no mote than 1%. This suggests that the proportion of the whole brain metabolism utilized regionally is stable in a group of subjects over time. Both groups of subjects had lower morning than afternoon metabolism, but the differences were slight in the p.m.-a.m. group. One measure of anxiety (pulse at fun 1) was correlated with run 1 metabolism and with the percentage of change from run 1 to run 2. No significant run 2 correlations were observed. This is the first study to measure test-retest variability in cerebral glucose metabolism in a large sample of young normal subjects. It demonstrates that the deoxyglucose method yields low Intrasubject variability and high stability over a 24-h period.

scholarly journals Impaired perceptual learning in Fragile X syndrome is mediated by parvalbumin neuron dysfunction in V1 and is reversible

2017 ◽  
Author(s):  
Anubhuti Goel ◽  
Daniel A. Cantu ◽  
Janna Guilfoyle ◽  
Gunvant R. Chaudhari ◽  
Aditi Newadkar ◽  
...  
Keyword(s):  
Perceptual Learning ◽  
Fragile X Syndrome ◽  
Visual Discrimination ◽  
Fragile X ◽  
Human Subjects ◽  
Autistic Traits ◽  
Autism Spectrum ◽  
Orientation Tuning ◽  
Mechanistic Basis

Atypical sensory processing is a core characteristic in autism spectrum disorders1 that negatively impacts virtually all activities of daily living. Sensory symptoms are predictive of the subsequent appearance of impaired social behavior and other autistic traits2, 3. Thus, a better understanding of the changes in neural circuitry that disrupt perceptual learning in autism could shed light into the mechanistic basis and potential therapeutic avenues for a range of autistic symptoms2. Likewise, the lack of directly comparable behavioral paradigms in both humans and animal models currently limits the translational potential of discoveries in the latter. We adopted a symptom-to-circuit approach to uncover the circuit-level alterations in the Fmr1-/- mouse model of Fragile X syndrome (FXS) that underlie atypical visual discrimination in this disorder4, 5. Using a go/no-go task and in vivo 2-photon calcium imaging in primary visual cortex (V1), we find that impaired discrimination in Fmr1-/- mice correlates with marked deficits in orientation tuning of principal neurons, and a decrease in the activity of parvalbumin (PV) interneurons in V1. Restoring visually evoked activity in PV cells in Fmr1-/- mice with a chemogenetic (DREADD) strategy was sufficient to rescue their behavioral performance. Finally, we found that human subjects with FXS exhibit strikingly similar impairments in visual discrimination as Fmr1-/- mice. We conclude that manipulating orientation tuning in autism could improve visually guided behaviors that are critical for playing sports, driving or judging emotions.

scholarly journals Genetic removal of p70 S6K1 corrects coding sequence length-dependent alterations in mRNA translation in fragile X syndrome mice

2020 ◽  
Author(s):  
Sameer Aryal ◽  
Francesco Longo ◽  
Eric Klann
Keyword(s):  
Protein Synthesis ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Mrna Translation ◽  
Ribosome Profiling ◽  
Sequence Length ◽  
Rna Seq ◽  
Double Knockout ◽  
Coding Sequence ◽  
Mental Retardation Protein

AbstractLoss of the fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS). FMRP is widely thought to repress protein synthesis, but its translational targets and modes of control remain in dispute. We previously showed that genetic removal of p70 S6 kinase 1 (S6K1) corrects altered protein synthesis as well as synaptic and behavioral phenotypes in FXS mice. In this study, we examined the gene-specificity of altered mRNA translation in FXS and the mechanism of rescue with genetic reduction of S6K1 by carrying out ribosome profiling and RNA-Seq on cortical lysates from wild-type, FXS, S6K1 knockout, and double knockout mice. We observed reduced ribosome footprint abundance in the majority of differentially translated genes in the cortices of FXS mice. We used molecular assays to discover evidence that the reduction in ribosome footprint abundance reflects an increased rate of ribosome translocation, which is captured as a decrease in the number of translating ribosomes at steady state, and is normalized by inhibition of S6K1. We also found that genetic removal of S6K1 prevented a positive-to-negative gradation of alterations in translation efficiencies (RF/mRNA) with coding sequence length across mRNAs in FXS mouse cortices. Our findings reveal the identities of dysregulated mRNAs and a molecular mechanism by which reduction of S6K1 prevents altered translation in FXS.

scholarly journals Fragile X syndrome patient-derived neurons developing in the mouse brain show FMR1 -dependent phenotypes

2021 ◽  
Author(s):  
Marine A Krzisch ◽  
Hao A Wu ◽  
Bingbing Yuan ◽  
Troy W. Whitfield ◽  
X. Shawn Liu ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Neuronal Development ◽  
Fragile X ◽  
In Vitro Models ◽  
Synaptic Activity ◽  
Human Neurons ◽  
Induced Pluripotent ◽  
And Function ◽  
The Brain

Abnormal neuronal development in Fragile X syndrome (FXS) is poorly understood. Data on FXS patients remain scarce and FXS animal models have failed to yield successful therapies. In vitro models do not fully recapitulate the morphology and function of human neurons. Here, we co-injected neural precursor cells (NPCs) from FXS patient-derived and corrected isogenic control induced pluripotent stem cells into the brain of neonatal immune-deprived mice. The transplanted cells populated the brain and a proportion differentiated into neurons and glial cells. Single-cell RNA sequencing of transplanted cells revealed upregulated excitatory synaptic transmission and neuronal differentiation pathways in FXS neurons. Immunofluorescence analyses showed accelerated maturation of FXS neurons after an initial delay. Additionally, increased percentages of Arc- and Egr1-positive FXS neurons and wider dendritic protrusions of mature FXS striatal medium spiny neurons pointed to an increase in synaptic activity and synaptic strength as compared to control. This transplantation approach provides new insights into the alterations of neuronal development in FXS by facilitating physiological development of cells in a 3D context, and could be used to test new therapeutic compounds correcting neuronal development defects in FXS.

scholarly journals In vivo Cerebral Protein Synthesis Rates with Leucyl-Transfer RNA Used as a Precursor Pool: Determination of Biochemical Parameters to Structure Tracer Kinetic Models for Positron Emission Tomography

1989 ◽  
Vol 9 (4) ◽  
pp. 429-445 ◽  
Author(s):  
Randy E. Keen ◽  
Jorge R. Barrio ◽  
Sung-Cheng Huang ◽  
Randall A. Hawkins ◽  
Michael E. Phelps
Keyword(s):  
Positron Emission Tomography ◽  
Protein Synthesis ◽  
Bolus Injection ◽  
Emission Tomography ◽  
Precursor Pool ◽  
Leucine Oxidation ◽  
Positron Emission ◽  
Tissue Compartments ◽  
Cerebral Protein Synthesis

Leucine oxidation and incorporation into proteins were examined in the in vivo rat brain to determine rates and compartmentation of these processes for the purpose of structuring mathematical compartmental models for the noninvasive estimation of in vivo human cerebral protein synthesis rates (CPSR) using positron emission tomography (PET). Leucine specific activity (SA) in arterial plasma and intracellular free amino acids, leucyl-tRNA, α-ketoisocaproic acid (KIC), and protein were determined in whole brain of the adult rat during the first 35 min after intravenous bolus injection of l-[1-14C]leucine. Incorporation of leucine into proteins accounted for 90% of total brain radioactivity at 35 min. The lack of [14C]KIC buildup indicates that leucine oxidation in brain is transaminase limited. Characteristic specific activities were maximal between 0 to 2 min after bolus injection with subsequent decline following the pattern: plasma leucine ≥ leucyl-tRNA ≈ KIC > intracellular leucine. The time integral of leucine SA in plasma was about four times that of tissue leucine and twice those of leucyl-tRNA and KIC, indicating the existence of free leucine, leucyl-tRNA, and KIC tissue compartments, communicating directly with plasma, and separate secondary free leucine, leucyl-tRNA, and KIC tissue compartments originating in unlabeled leucine from proteolysis. Therefore, a relatively simple model configuration based on the key assumptions that (a) protein incorporation and catabolism proceed from a precursor pool communicating with the plasma space, and (b) leucine catabolism is transaminase limited is justified for the in vivo assessment of CPSR from exogenous leucine sources using PET in humans.

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