"Trouble du spectre de l'autisme": neuropathologie et modèles animaux

Aperçu: G.M.

Le "trouble du spectre de l'autisme"  (TSA) a un impact majeur sur le développement et l'intégration sociale des personnes touchées et est le plus héritable des troubles psychiatriques. Une augmentation de l'incidence des cas de TSA a provoqué une poussée des efforts de recherche sur les processus neuropathologiques sous-jacents. L'équipe présente un aperçu des résultats actuels dans les études sur la neuropathologie des TSA en utilisant deux approches expérimentales, les cerveaux humains post-mortem et les modèles animaux de TSA, et discute des chevauchements, des limites et de la signification de chacun.

L'examen post-mortem des cerveaux TSA a révélé des changements globaux, y compris des matières grasses et blanches désorganisées, un nombre accru de neurones, une diminution du volume de soma neuronal  et une augmentation du neuropil (Note de trad. source Wikipédia: le neuropile est la partie du tissu nerveux située entre les principales cellules constituant la substance grise du système nerveux central. ), les derniers changements dans les densités des épines dendritiques, la vascularisation cérébrale et la glie. Les zones corticales et non corticales montrent des anomalies spécifiques  dans la morphologie neuronale et l'organisation cytoarchitecturale, avec des résultats cohérents rapportés pour le cortex préfrontal, le gyrus fusiforme, le cortex fronto-intestinal, le cortex cingulé, l'hippocampe, l'amygdale, le cervelet et le tronc cérébral. 

Les modèles animaux génétiquement modifiés comprennent ceux basés sur des gènes ASD monogènes bien étudiés (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, FMR1, TSC1 / 2), les nouveaux gènes de risque (CHD8, SCN2A, SYNGAP1, ARID1B, GRIN2B, DSCAM, TBR1 ) et les variations du nombre de copie (suppression 15q11-q13, microdélétion 15q13.3, duplication 15q11-13, suppression 16p11.2 et duplication, suppression 22q11.2). 

 

Acta Neuropathol. 2017 Jun 5. doi: 10.1007/s00401-017-1736-4.

Autism spectrum disorder: neuropathology and animal models

Varghese M^1,2, Keshav N^1,2,3, Jacot-Descombes S^1,2,4, Warda T^1,2, Wicinski B^1,2, Dickstein DL^1,2,5, Harony-Nicolas H^3,6, De Rubeis S^3,6, Drapeau E^3,6, Buxbaum JD^1,2,3,6, Hof PR^7,8,9.

Author information

1

Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, Box 1639, One Gustave L. Levy Place, New York, NY, 10029, USA.

2

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

3

Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

4

Unit of Psychiatry, Department of Children and Teenagers, University Hospitals and School of Medicine, Geneva, CH-1205, Switzerland.

5

Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.

6

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

7

Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, Box 1639, One Gustave L. Levy Place, New York, NY, 10029, USA. patrick.hof@mssm.edu.

8

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. patrick.hof@mssm.edu.

9

Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. patrick.hof@mssm.edu.

Abstract

Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations, and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectural organization, with consistent findings reported from the prefrontal cortex, fusiform gyrus, frontoinsular cortex, cingulate cortex, hippocampus, amygdala, cerebellum and brainstem. The paucity of postmortem human studies linking neuropathology to the underlying etiology has been partly addressed using animal models to explore the impact of genetic and non-genetic factors clinically relevant for the ASD phenotype. Genetically modified models include those based on well-studied monogenic ASD genes (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, FMR1, TSC1/2), emerging risk genes (CHD8, SCN2A, SYNGAP1, ARID1B, GRIN2B, DSCAM, TBR1), and copy number variants (15q11-q13 deletion, 15q13.3 microdeletion, 15q11-13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal exposure to sodium valproate, maternal autoantibodies, and maternal immune activation. In addition to replicating some of the neuropathologic features seen in postmortem studies, a common finding in several animal models of ASD is altered density of dendritic spines, with the direction of the change depending on the specific genetic modification, age and brain region. Overall, postmortem neuropathologic studies with larger sample sizes representative of the various ASD risk genes and diverse clinical phenotypes are warranted to clarify putative etiopathogenic pathways further and to promote the emergence of clinically relevant diagnostic and therapeutic tools. In addition, as genetic alterations may render certain individuals more vulnerable to developing the pathological changes at the synapse underlying the behavioral manifestations of ASD, neuropathologic investigation using genetically modified animal models will help to improve our understanding of the disease mechanisms and enhance the development of targeted treatments.

PMID: 28584888

DOI: 10.1007/s00401-017-1736-4