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Autism spectrum disorder: neuropathology and animal models.

Authors
  • Varghese, Merina1, 2
  • Keshav, Neha1, 2, 3
  • Jacot-Descombes, Sarah1, 2, 4
  • Warda, Tahia1, 2
  • Wicinski, Bridget1, 2
  • Dickstein, Dara L1, 2, 5
  • Harony-Nicolas, Hala3, 6
  • De Rubeis, Silvia3, 6
  • Drapeau, Elodie3, 6
  • Buxbaum, Joseph D1, 2, 3, 6
  • Hof, Patrick R7, 8, 9
  • 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. , (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. [email protected]
  • 8 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. [email protected]
  • 9 Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. [email protected]
Type
Published Article
Journal
Acta Neuropathologica
Publisher
Springer-Verlag
Publication Date
Oct 01, 2017
Volume
134
Issue
4
Pages
537–566
Identifiers
DOI: 10.1007/s00401-017-1736-4
PMID: 28584888
Source
Medline
Keywords
Language
English
License
Unknown

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.

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