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 M1,2, Keshav N1,2,3, Jacot-Descombes S1,2,4, Warda T1,2, Wicinski B1,2, Dickstein DL1,2,5, Harony-Nicolas H3,6, De Rubeis S3,6, Drapeau E3,6, Buxbaum JD1,2,3,6, Hof PR7,8,9.
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
