Pubmed du 24/05/13

Pubmed du jour

2013-05-24 12:03:50

1. Lohith TG, Osterweil EK, Fujita M, Jenko KJ, Bear MF, Innis RB. {{Is metabotropic glutamate receptor 5 upregulated in prefrontal cortex in fragile X syndrome?}}. {Molecular autism}. 2013 May 24;4(1):15.

BACKGROUND: Fragile X syndrome (FXS) is a common inherited form of intellectual disability caused by loss of function of the fragile X mental retardation protein. Recent animal studies suggest that upregulated downstream signaling by metabotropic glutamate receptor 5 (mGluR5) might be an important mechanism for cognitive and behavioral abnormalities associated with FXS. However, mGluR5 density in human FXS remains unknown. METHODS: Receptor binding and protein expression were measured in the postmortem prefrontal cortex of 14 FXS patients or carriers and 17 age- and sex-matched control subjects without neurological disorders. In-vitro binding assays were performed using [3H]-labeled 3-methoxy-5-pyridin-2-ylethynylpyridine (MPEPy), a selective and high-affinity negative allosteric modulator of mGluR5, to measure receptor density and the radioligand’s dissociation constant, which is inversely proportional to affinity. Immunoblotting was also performed, to measure mGluR5 protein expression. RESULTS: The mGluR5 density increased with marginal significance (+16%; P = 0.058) in the prefrontal cortex of FXS patients or carriers compared with matched healthy controls. No significant change in dissociation constant (-4%; P = 0.293) was observed. Immunoblotting found a significant elevation (+32%; P = 0.048) in mGluR5 protein expression. CONCLUSIONS: Both mGluR5 binding density and protein expression were increased in the brains of FXS patients or carriers, but only expression was significantly different, which could be because of the small sample size and moderate variability. Another important caveat is that the effects of psychotropic medications on mGluR5 expression are largely unknown. Future in-vivo measurement of mGluR5 with positron emission tomography might characterize the role of this receptor in the pathophysiology of FXS and facilitate trials of mGluR5-oriented treatments for this disorder.

Lien vers le texte intégral (Open Access ou abonnement)

2. Miltenberger CA, Charlop MH. {{Increasing the Athletic Group Play of Children with Autism}}. {J Autism Dev Disord}. 2013 May 23.

A multiple baseline design across three children with autism and within child across activity was used to assess the effects of interventions designed to teach children with autism to play two common athletic group games, handball and 4-square. Treatment consisted of two phases. In Phase I, athletic skills training, the children participated in sessions designed facilitate their acquisition of the athletic skills required by the targeted games. During Phase II, rules training, the children were instructed on the rules of the targeted games. Mastering the athletic skills and participating in rules training resulted in increased athletic group play and concomitant increases in speech. These gains were maintained at 8-16 weeks follow-up. However, generalization to participation in school recess activities did not occur.

Lien vers le texte intégral (Open Access ou abonnement)

3. Sarachana T, Hu VW. {{Genome-wide identification of transcriptional targets of RORA reveals direct regulation of multiple genes associated with autism spectrum disorder}}. {Molecular autism}. 2013 May 22;4(1):14.

BACKGROUND: We have recently identified the nuclear hormone receptor RORA (retinoic acid-related orphan receptor-alpha) as a novel candidate gene for autism spectrum disorder (ASD). Our independent cohort studies have consistently demonstrated the reduction of RORA transcript and/or protein levels in blood-derived lymphoblasts as well as in the postmortem prefrontal cortex and cerebellum of individuals with ASD. Moreover, we have also shown that RORA has the potential to be under negative and positive regulation by androgen and estrogen, respectively, suggesting the possibility that RORA may contribute to the male bias of ASD. However, little is known about transcriptional targets of this nuclear receptor, particularly in humans. METHODS: Here we identify transcriptional targets of RORA in human neuronal cells on a genome-wide level using chromatin immunoprecipitation (ChIP) with an anti-RORA antibody followed by whole-genome promoter array (chip) analysis. Selected potential targets of RORA were then validated by an independent ChIP followed by quantitative PCR analysis. To further demonstrate that reduced RORA expression results in reduced transcription of RORA targets, we determined the expression levels of the selected transcriptional targets in RORA-deficient human neuronal cells, as well as in postmortem brain tissues from individuals with ASD who exhibit reduced RORA expression. RESULTS: The ChIP-on-chip analysis reveals that RORA1, a major isoform of RORA protein in human brain, can be recruited to as many as 2,764 genomic locations corresponding to promoter regions of 2,544 genes across the human genome. Gene ontology analysis of this dataset of genes that are potentially directly regulated by RORA1 reveals statistically significant enrichment in biological functions negatively impacted in individuals with ASD, including neuronal differentiation, adhesion and survival, synaptogenesis, synaptic transmission and plasticity, and axonogenesis, as well as higher level functions such as development of the cortex and cerebellum, cognition, memory, and spatial learning. Independent ChIP-quantitative PCR analyses confirm binding of RORA1 to promoter regions of selected ASD-associated genes, including A2BP1, CYP19A1, ITPR1, NLGN1, and NTRK2, whose expression levels (in addition to HSD17B10) are also decreased in RORA1-repressed human neuronal cells and in prefrontal cortex tissues from individuals with ASD. CONCLUSIONS: Findings from this study indicate that RORA transcriptionally regulates A2BP1, CYP19A1, HSD17B10, ITPR1, NLGN1, and NTRK2, and strongly suggest that reduction of this sex hormone-sensitive nuclear receptor in the brain causes dysregulated expression of these ASD-relevant genes as well as their associated pathways and functions which, in turn, may contribute to the underlying pathobiology of ASD.

Lien vers le texte intégral (Open Access ou abonnement)

4. Tottenham N, Hertzig ME, Gillespie-Lynch K, Gilhooly T, Millner AJ, Casey BJ. {{Elevated amygdala response to faces and gaze aversion in autism spectrum disorder}}. {Social cognitive and affective neuroscience}. 2013 May 24.

Autism spectrum disorders (ASD) are often associated with impairments in judgment of facial expressions. This impairment is often accompanied by diminished eye contact and atypical amygdala responses to face stimuli. The current study used a within-subjects design to examine the effects of natural viewing and an experimental eye-gaze manipulation on amygdala responses to faces. Individuals with ASD showed less gaze toward the eye region of faces relative to a control group. Among individuals with ASD, reduced eye gaze was associated with higher threat ratings of neutral faces. Amygdala signal was elevated in the ASD group relative to controls. This elevated response was further potentiated by experimentally manipulating gaze to the eye region. Potentiation by the gaze manipulation was largest for those individuals who exhibited the least amount of naturally occurring gaze toward the eye region and was associated with their subjective threat ratings. Effects were largest for neutral faces, highlighting the importance of examining neutral faces in the pathophysiology of autism and questioning their use as control stimuli with this population. Overall, our findings provide support for the notion that gaze direction modulates affective response to faces in ASD.

Lien vers le texte intégral (Open Access ou abonnement)

5. Zuddas A. {{Autism assessment tools in the transition from DSM-IV to DSM-5}}. {European child & adolescent psychiatry}. 2013 May 24.

Lien vers le texte intégral (Open Access ou abonnement)