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

L'expression d'une mutation DISC1 dans les cellules de Purkinje augmente leur activité spontanée et affecte les comportements cognitifs et sociaux chez la souris

Aperçu: G.M.

En plus de la fonction motrice, le cervelet a été impliqué dans les comportements cognitifs et sociaux. Diverses anomalies structurelles et fonctionnelles des cellules de Purkinje (PC) ont été observées dans la schizophrénie et l'autisme.

Les résultats indiquent que le DISC1 mutant modifie la physiologie des PC, ce qui peut conduire à une mémoire de reconnaissance anormale chez la souris.

Neurobiol Dis. 2017 Apr 6. pii: S0969-9961(17)30082-7. doi: 10.1016/j.nbd.2017.04.008.

Expression of mutant DISC1 in Purkinje cells increases their spontaneous activity and impairs cognitive and social behaviors in mice

Shevelkin AV¹, Terrillion CE², Abazyan BN², Kajstura TJ³, Jouroukhin YA², Rudow GL⁴, Troncoso JC⁴, Linden DJ³, Pletnikov MV⁵.

Author information

1

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; P.K. Anokhin Research Institute of Normal Physiology, Moscow, Russian Federation.

2

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

3

Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

4

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

5

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: mpletnik@jhmi.edu

Abstract

In addition to motor function, the cerebellum has been implicated in cognitive and social behaviors. Various structural and functional abnormalities of Purkinje cells (PCs) have been observed in schizophrenia and autism. As PCs express the gene Disrupted-In-Schizophrenia-1 (DISC1), and DISC1 variants have been associated with neurodevelopmental disorders, we evaluated the role of DISC1 in cerebellar physiology and associated behaviors using a mouse model of inducible and selective expression of a dominant-negative, C-terminus truncated human DISC1 (mutant DISC1) in PCs. Mutant DISC1 male mice demonstrated impaired social and novel placement recognition. No group differences were found in novelty-induced hyperactivity, elevated plus maze test, spontaneous alternation, spatial recognition in Y maze, sociability or accelerated rotarod. Expression of mutant DISC1 was associated with a decreased number of large somata PCs (volume: 3000-5000μm³) and an increased number of smaller somata PCs (volume: 750-1000μm³) without affecting the total number of PCs or the volume of the cerebellum. Compared to control mice, attached loose patch recordings of PCs in mutant DISC1 mice revealed increased spontaneous firing of PCs; and whole cell recordings showed increased amplitude and frequency of mEPSCs without significant changes in either R_input or parallel fiber EPSC paired-pulse ratio. Our findings indicate that mutant DISC1 alters the physiology of PCs, possibly leading to abnormal recognition memory in mice.

Copyright © 2017. Published by Elsevier Inc.

PMID: 28392471

DOI: 10.1016/j.nbd.2017.04.008

La signalisation placentaire interleukine-6 contrôle le développement et le comportement du cerveau du foetus

Aperçu: G.M.

Des études épidémiologiques montrent que l'activation immunitaire maternelle (MIA) pendant la grossesse est un facteur de risque pour l'autisme. Cependant, les mécanismes de la MIA affectant le développement du cerveau et les comportements chez les descendants restent mal décrits.

Les résultats de l'étude démontrent que l'activation de l'IL-6 dans le placenta est nécessaire pour transmettre les signaux inflammatoires au cerveau fœtal et les comportements et les neuropathologies affectant le trouble neuro-dévelopemental. 

Brain Behav Immun. 2017 May;62:11-23. doi: 10.1016/j.bbi.2016.11.007. Epub 2016 Nov 9.

The placental interleukin-6 signaling controls fetal brain development and behavior

Wu WL¹, Hsiao EY², Yan Z³, Mazmanian SK⁴, Patterson PH⁵.

Author information

1

Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125, USA. Electronic address: wlwu@caltech.edu

2

Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125, USA; Department of Integrative Biology & Physiology, University of California, Los Angeles, 610 Charles E. Young Drive, Los Angeles, CA 90095, USA. Electronic address: ehsiao@ucla.edu.

3

Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125, USA. Electronic address: Zihao_Yan@hms.harvard.edu.

4

Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125, USA. Electronic address: sarkis@caltech.edu.

5

Division of Biology and Biological Engineering, California Institute of Technology, 1200 E. California Boulevard, Pasadena, CA 91125, USA. Electronic address: php@caltech.edu.

Abstract

Epidemiological studies show that maternal immune activation (MIA) during pregnancy is a risk factor for autism. However, mechanisms for how MIA affects brain development and behaviors in offspring remain poorly described. To determine whether placental interleukin-6 (IL-6) signaling is required for mediating MIA on the offspring, we generated mice with restricted deletion of the receptor for IL-6 (IL-6Rα) in placental trophoblasts (Cyp19-Cre⁺;Il6ra^fl/fl), and tested offspring of Cyp19-Cre⁺;Il6ra^fl/fl mothers for immunological, pathological and behavioral abnormalities following induction of MIA. We reveal that MIA results in acute inflammatory responses in the fetal brain. Lack of IL-6 signaling in trophoblasts effectively blocks MIA-induced inflammatory responses in the placenta and the fetal brain. Furthermore, behavioral abnormalities and cerebellar neuropathologies observed in MIA control offspring are prevented in Cyp19-Cre⁺;Il6ra^fl/fl offspring. Our results demonstrate that IL-6 activation in placenta is required for relaying inflammatory signals to the fetal brain and impacting behaviors and neuropathologies relevant to neurodevelopmental disease.

Copyright © 2016 Elsevier Inc. All rights reserved.

PMID: 27838335

DOI: 10.1016/j.bbi.2016.11.007