Pubmed du 14/04/19

dimanche 14 avril 2019

1. Bowling H, Bhattacharya A, Zhang G, Alam D, Lebowitz JZ, Bohm-Levine N, Lin D, Singha P, Mamcarz M, Puckett R, Zhou L, Aryal S, Sharp K, Kirshenbaum K, Berry-Kravis E, Neubert TA, Klann E. Altered steady state and activity-dependent de novo protein expression in fragile X syndrome. Nat Commun. 2019 ; 10(1) : 1710.

Whether fragile X mental retardation protein (FMRP) target mRNAs and neuronal activity contributing to elevated basal neuronal protein synthesis in fragile X syndrome (FXS) is unclear. Our proteomic experiments reveal that the de novo translational profile in FXS model mice is altered at steady state and in response to metabotropic glutamate receptor (mGluR) stimulation, but the proteins expressed differ under these conditions. Several altered proteins, including Hexokinase 1 and Ras, also are expressed in the blood of FXS model mice and pharmacological treatments previously reported to ameliorate phenotypes modify their abundance in blood. In addition, plasma levels of Hexokinase 1 and Ras differ between FXS patients and healthy volunteers. Our data suggest that brain-based de novo proteomics in FXS model mice can be used to find altered expression of proteins in blood that could serve as disease-state biomarkers in individuals with FXS.

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4. Ibrahim K, Eilbott JA, Ventola P, He G, Pelphrey KA, McCarthy G, Sukhodolsky DG. Reduced Amygdala-Prefrontal Functional Connectivity in Children With Autism Spectrum Disorder and Co-occurring Disruptive Behavior. Biol Psychiatry Cogn Neurosci Neuroimaging. 2019.

BACKGROUND : Disruptive behaviors are prevalent in children with autism spectrum disorder (ASD) and often cause substantial impairments. However, the underlying neural mechanisms of disruptive behaviors remain poorly understood in ASD. In children without ASD, disruptive behavior is associated with amygdala hyperactivity and reduced connectivity with the ventrolateral prefrontal cortex (vlPFC). This study examined amygdala reactivity and connectivity in children with ASD with and without co-occurring disruptive behavior disorders. We also investigated differential contributions of externalizing behaviors and callous-unemotional traits to variance in amygdala connectivity and reactivity. METHODS : This cross-sectional study involved behavioral assessments and neuroimaging in three groups of children 8 to 16 years of age : 18 children had ASD and disruptive behavior, 20 children had ASD without disruptive behavior, and 19 children were typically developing control participants matched for age, gender, and IQ. During functional magnetic resonance imaging, participants completed an emotion perception task of fearful versus calm faces. Task-specific changes in amygdala reactivity and connectivity were examined using whole-brain, psychophysiological interaction, and multiple regression analyses. RESULTS : Children with ASD and disruptive behavior showed reduced amygdala-vlPFC connectivity compared with children with ASD without disruptive behavior. Externalizing behaviors and callous-unemotional traits were associated with amygdala reactivity to fearful faces in children with ASD after controlling for suppressor effects. CONCLUSIONS : Reduced amygdala-vlPFC connectivity during fear processing may differentiate children with ASD and disruptive behavior from children with ASD without disruptive behavior. The presence of callous-unemotional traits may have implications for identifying differential patterns of amygdala activity associated with increased risk of aggression in ASD. These findings suggest a neural mechanism of emotion dysregulation associated with disruptive behavior in children with ASD.

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6. Mahdavinasab SM, Saghazadeh A, Motamed-Gorji N, Vaseghi S, Mohammadi MR, Alichani R, Akhondzadeh S. Baclofen as an adjuvant therapy for autism : a randomized, double-blind, placebo-controlled trial. Eur Child Adolesc Psychiatry. 2019.

Increasing evidence suggests that the function of the GABAergic system is abnormally low in autism spectrum disorder (ASD). Baclofen, which functions as a selective agonist for GABAB receptors, does appear promising for the treatment of ASD. We conducted a 10-week randomized-controlled study aimed at evaluating the potential of baclofen as an adjuvant therapy to enhance the effect of risperidone in children with ASD. Sixty-four children (3-12 years) with moderate-to-severe irritability symptoms of ASD were included. We used the Aberrant Behavior Checklist-Community Edition (ABC-C) for the outcome measures on each of the follow-up visits (weeks 0, 5, and 10). Analysis of the combined data revealed significant improvement for all the ABC subscales (irritability : F = 51.644, df = 1.66, p < 0.001, lethargy : F = 39.734, df = 1.38, p < 0.001, stereotypic behavior : F = 25.495, df = 1.56, p < 0.001, hyperactivity : F = 54.135, df = 1.35, p < 0.001, and inappropriate speech : F = 19.277, df = 1.47, p = 0.004). Combined treatment with baclofen and risperidone exerted a greater effect on improvement of hyperactivity symptoms at both midpoint [Cohen’s d, 95% confidence interval (CI) = - 3.14, - 5.56 to - 0.72] and endpoint (d, 95% CI = - 4.45, - 8.74 to - 0.16) when compared with treatment with placebo plus risperidone. The two treatments achieved comparable results for other outcome measures. Our data support safety and efficacy of baclofen as an adjuvant to risperidone for improvement of hyperactivity symptoms in children with ASD.

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8. Walker SJ, Langefeld CD, Zimmerman K, Schwartz MZ, Krigsman A. A molecular biomarker for prediction of clinical outcome in children with ASD, constipation, and intestinal inflammation. Sci Rep. 2019 ; 9(1) : 5987.

In children with autism spectrum disorder (ASD) who present to the gastroenterologist with chronic constipation on a background of colonic inflammation, we have identified two distinct clinical subtypes : (1) patients who experience a sustained state of GI symptomatic remission while on maintenance anti-inflammatory therapy (fast responders) and, (2) those with recurrent right-sided fecal loading requiring regular colon cleanouts during treatment for enterocolitis (slow responders). We hypothesized that a detailed molecular analysis of tissue from the affected region of the colon would provide mechanistic insights regarding the fast versus slow response to anti-inflammatory therapy. To test this, ascending colon biopsy tissues from 35 children with ASD (20 slow responders and 15 fast responders) were analyzed by RNAseq. Hierarchical cluster analysis was performed to assign samples to clusters and gene expression analysis was performed to identify differentially expressed transcripts (DETs) between samples within the clusters. Significant differences were found between the two clusters with fast responder-predominant cluster showing an upregulation of transcripts involved in the activation of immune and inflammatory response and the slow responder-predominant cluster showing significant over-representation of pathways impacting colonic motility (e.g. genes involved in tryptophan and serotonin degradation and mitochondrial dysfunction). Regression analysis identified a single long non-coding RNA that could predict cluster assignment with a high specificity (0.88), sensitivity (0.89) and accuracy (0.89). Comparison of gene expression profiles in the ascending colon from a subset of patients with ASD, chronic right-sided fecal loading constipation and a slow versus fast response to therapy has identified molecular mechanisms that likely contribute to this differential response following the primary therapeutic intervention (i.e. treatment for colonic inflammation with brief induction immunosuppression followed by maintenance non-steroidal anti-inflammatory therapy). Importantly, we have identified a transcript that, if validated, may provide a biomarker that can predict from the outset which patients will be slow responders who would benefit from an alternate therapeutic strategy in treating their constipation.

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9. Zhang X, Piano I, Messina A, D’Antongiovanni V, Cro F, Provenzano G, Bozzi Y, Gargini C, Casarosa S. Retinal Defects in Mice Lacking the Autism-Associated Gene Engrailed-2. Neuroscience. 2019.

Defective cortical processing of visual stimuli and altered retinal function have been described in autism spectrum disorder (ASD) patients. In keeping with these findings, anatomical and functional defects have been found in the visual cortex and retina of mice bearing mutations for ASD-associated genes. Here we sought to investigate the anatomy and function of the adult retina of Engrailed 2 knockout (En2(-/-)) mice, a model for ASD. Our results showed that En2 is expressed in all three nuclear layers of the adult retina. When compared to age-matched En2(+/+) controls, En2(-/-) adult retinas showed a significant decrease in the number of calbindin(+) horizontal cells, and a significant increase in calbindin(+) amacrine/ganglion cells. The total number of ganglion cells was not altered in the adult En2(-/-) retina, as shown by Brn3a(+) cell counts. In addition, En2(-/-) adult mice showed a significant reduction of photoreceptor (rhodopsin) and bipolar cell (Pcp2, PKCalpha) markers. Functional defects were also present in the retina of En2 mutants, as indicated by electroretinogram recordings showing a significant reduction in both a-wave and b-wave amplitude in En2(-/-) mice as compared to controls. These data show for the first time that anatomical and functional defects are present in the retina of the En2 ASD mouse model.

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