Diminution des niveaux d'ARNm de la parvalbumine dans les cellules cérébelleuses de Purkinje dans l'autisme

Aperçu: G.M.

Des études récentes de neuropathologie du cerveau humain indiquent que plusieurs régions du cortex préfrontal ont vu une diminution du nombre d'interneurones de parvalbumine ou une diminution de l'expression de la parvalbumine dans les "troubles du spectre de l'autisme" (TSA).

Ces données suggèrent qu'un déficit de parvalbumine peut être une neuropathologie clé du TSA et contribuer à l'altération de l'inhibition GABAergique . Cependant, on ne sait pas si un déficit de parvalbumine est un phénomène qui se produit dans des régions autres que le cortex cérébral. Le cervelet est une région majeure où la neuropathologie a été détectée pour la première fois chez les TSA il y a plus de trois décennies. L'objectif de la présente étude était de déterminer si l'expression du gène parvalbumine est également modifiée dans les neurones de Purkinje du cervelet. 

Les résultats indiquent que les niveaux d'ARNm de parvalbumine sont significativement plus faibles dans les cellules de Purkinje dans le TSA que chez les témoins. Cette diminution n'a pas été influencée par l'intervalle post-mortem ou l'âge du décès. 

Ce résultat indique que l'expression réduite de la parvalbumine est une caractéristique plus répandue du TSA.

Autism Res. 2017 Jul 14. doi: 10.1002/aur.1835.

Decreased parvalbumin mRNA levels in cerebellar Purkinje cells in autism

Soghomonian JJ¹, Zhang K¹, Reprakash S¹, Blatt GJ².

Author information

1

Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts.

2

Hussman Institute for Autism, Program in Neuroscience, Baltimore, Maryland.

Abstract

Recent neuropathology studies in human brains indicate that several areas of the prefrontal cortex have decreased numbers of parvalbumin interneurons or decreased parvalbumin expression in Autism Spectrum disorders (ASD) [Hashemi, Ariza, Rogers, Noctor, & Martinez-Cerdeno, 2017; Zikopoulos & Barbas, ]. These data suggest that a deficit in parvalbumin may be a key neuropathology of ASD and contribute to altered GABAergic inhibition. However, it is unclear if a deficit in parvalbumin is a phenomenon that occurs in regions other than the cerebral cortex. The cerebellum is a major region where neuropathology was first detected in ASD over three decades ago [Bauman & Kemper, ]. In view of the documented association between parvalbumin-expressing neurons and autism, the objective of the present study was to determine if parvalbumin gene expression is also altered in Purkinje neurons of the cerebellum. Radioisotopic in situ hybridization histochemistry was used on human tissue sections from control and ASD brains in order to detect and measure parvalbumin mRNA levels at the single cell level in Purkinje cells of Crus II of the lateral cerebellar hemispheres. Results indicate that parvalbumin mRNA levels are significantly lower in Purkinje cells in ASD compared to control brains. This decrease was not influenced by post-mortem interval or age at death. This result indicates that decreased parvalbumin expression is a more widespread feature of ASD. We discuss how this decrease may be implicated in altered cerebellar output to the cerebral cortex and in key ASD symptoms. Autism Res 2017. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

© 2017 International Society for Autism Research, Wiley Periodicals, Inc.

PMID:28707805

DOI:10.1002/aur.1835

Comparaison transcriptomique du sang chez les personnes avec et sans diagnostic de trouble du spectre de l'autisme: une méga-analyse d'échantillons combinés

Aperçu: G.M.

Les études fondées sur les puces à ADN sur le sang comparant les personnes avec un diagnostic de trouble du spectre de l'autisme (TSA) et des personnes au développement typique aident à caractériser les différences dans les fonctions de cellules immunitaires circulantes et proposent un biomarqueur potentiel.

Am J Med Genet B Neuropsychiatr Genet. 2017 Apr;174(3):181-201. doi: 10.1002/ajmg.b.32511. Epub 2016 Nov 11.

Blood transcriptomic comparison of individuals with and without autism spectrum disorder: A combined-samples mega-analysis

Tylee DS¹, Hess JL¹, Quinn TP¹, Barve R¹, Huang H^2,3, Zhang-James Y¹, Chang J⁴, Stamova BS⁵, Sharp FR⁵, Hertz-Picciotto I⁶, Faraone SV^1,7, Kong SW⁸, Glatt SJ¹.

Author information

1

Departments of Psychiatry and Behavioral Sciences and Neuroscience and Physiology, Psychiatric Genetic Epidemiology and Neurobiology Laboratory (PsychGENe Lab), SUNY Upstate Medical University, Syracuse, New York.

2

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts.

3

Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

4

Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, New York.

5

Department of Neurology, UC Davis School of Medicine, Sacramento, California.

6

Department of Public Health Sciences and UC Davis MIND Institute, School of Medicine, Davis, California.

7

K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway.

8

Department of Pediatrics, Computational Health Informatics Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.

Abstract

Blood-based microarray studies comparing individuals affected with autism spectrum disorder (ASD) and typically developing individuals help characterize differences in circulating immune cell functions and offer potential biomarker signal. We sought to combine the subject-level data from previously published studies by mega-analysis to increase the statistical power. We identified studies that compared ex vivo blood or lymphocytes from ASD-affected individuals and unrelated comparison subjects using Affymetrix or Illumina array platforms. Raw microarray data and clinical meta-data were obtained from seven studies, totaling 626 affected and 447 comparison subjects. Microarray data were processed using uniform methods. Covariate-controlled mixed-effect linear models were used to identify gene transcripts and co-expression network modules that were significantly associated with diagnostic status. Permutation-based gene-set analysis was used to identify functionally related sets of genes that were over- and under-expressed among ASD samples. Our results were consistent with diminished interferon-, EGF-, PDGF-, PI3K-AKT-mTOR-, and RAS-MAPK-signaling cascades, and increased ribosomal translation and NK-cell related activity in ASD. We explored evidence for sex-differences in the ASD-related transcriptomic signature. We also demonstrated that machine-learning classifiers using blood transcriptome data perform with moderate accuracy when data are combined across studies. Comparing our results with those from blood-based studies of protein biomarkers (e.g., cytokines and trophic factors), we propose that ASD may feature decoupling between certain circulating signaling proteins (higher in ASD samples) and the transcriptional cascades which they typically elicit within circulating immune cells (lower in ASD samples). These findings provide insight into ASD-related transcriptional differences in circulating immune cells. © 2016 Wiley Periodicals, Inc.

© 2016 Wiley Periodicals, Inc.

PMID: 27862943

DOI: 10.1002/ajmg.b.32511