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Autism Spectrum Disorder: Neuropathology and Animal Models

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Autism Spectrum Disorder: Neuropathology and Animal Models Acta Neuropathol DOI 10.1007/s00401-017-1736-4 REVIEW Autism spectrum disorder: neuropathology and animal models Merina Varghese1,2 · Neha Keshav1,2,3 · Sarah Jacot‑Descombes1,2,5 · Tahia Warda1,2 · Bridget Wicinski1,2 · Dara L. Dickstein1,2,6 · Hala Harony‑Nicolas3,4 · Silvia De Rubeis3,4 · Elodie Drapeau3,4 · Joseph D. Buxbaum1,2,3,4 · Patrick R. Hof1,2,3 Received: 1 March 2017 / Revised: 30 May 2017 / Accepted: 31 May 2017 © Springer-Verlag GmbH Germany 2017 Abstract Autism spectrum disorder (ASD) has a major volume of neuronal soma, and increased neuropil, the last impact on the development and social integration of affected refecting changes in densities of dendritic spines, cerebral individuals and is the most heritable of psychiatric disorders. vasculature and glia. Both cortical and non-cortical areas An increase in the incidence of ASD cases has prompted a show region-specifc abnormalities in neuronal morphology surge in research efforts on the underlying neuropathologic and cytoarchitectural organization, with consistent fndings processes. We present an overview of current fndings in reported from the prefrontal cortex, fusiform gyrus, frontoin- neuropathology studies of ASD using two investigational sular cortex, cingulate cortex, hippocampus, amygdala, cer- approaches, postmortem human brains and ASD animal ebellum and brainstem. The paucity of postmortem human models, and discuss the overlap, limitations, and signif- studies linking neuropathology to the underlying etiology cance of each. Postmortem examination of ASD brains has been partly addressed using animal models to explore has revealed global changes including disorganized gray the impact of genetic and non-genetic factors clinically rel- and white matter, increased number of neurons, decreased evant for the ASD phenotype. Genetically modifed models include those based on well-studied monogenic ASD genes (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, Merina Varghese and Neha Keshav contributed equally. FMR1, TSC1/2), emerging risk genes (CHD8, SCN2A, SYN‑ Electronic supplementary material The online version of this GAP1, ARID1B, GRIN2B, DSCAM, TBR1), and copy num- article (doi:10.1007/s00401-017-1736-4) contains supplementary ber variants (15q11-q13 deletion, 15q13.3 microdeletion, material, which is available to authorized users. 15q11-13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred * Patrick R. Hof [email protected] rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal 1 Fishberg Department of Neuroscience, Icahn School exposure to sodium valproate, maternal autoantibodies, and of Medicine at Mount Sinai, Box 1639, One Gustave L. Levy maternal immune activation. In addition to replicating some Place, New York, NY 10029, USA of the neuropathologic features seen in postmortem stud- 2 Friedman Brain Institute, Icahn School of Medicine at Mount ies, a common fnding in several animal models of ASD is Sinai, New York, NY 10029, USA altered density of dendritic spines, with the direction of the 3 Seaver Autism Center for Research and Treatment, Icahn change depending on the specifc genetic modifcation, age School of Medicine at Mount Sinai, New York, NY 10029, USA and brain region. Overall, postmortem neuropathologic stud- ies with larger sample sizes representative of the various 4 Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA ASD risk genes and diverse clinical phenotypes are war- ranted to clarify putative etiopathogenic pathways further 5 Unit of Psychiatry, Department of Children and Teenagers, University Hospitals and School of Medicine, and to promote the emergence of clinically relevant diagnos- Geneva CH‑1205, Switzerland tic and therapeutic tools. In addition, as genetic alterations 6 Department of Pathology, Uniformed Services University may render certain individuals more vulnerable to develop- of the Health Sciences, Bethesda, MD 20814, USA ing the pathological changes at the synapse underlying the 1 3 Acta Neuropathol behavioral manifestations of ASD, neuropathologic investi- Introduction gation using genetically modifed animal models will help to improve our understanding of the disease mechanisms and Autism spectrum disorder (ASD) is typically diagnosed enhance the development of targeted treatments. within the frst three years of life, and is defned by per- sistent defcits in social communication and interaction, Keywords Autism spectrum disorder · Cerebral as well as restrictive and repetitive behaviors [8]. ASD cortex · Genetically modifed animal models · Neuronal affects 1 in 68 children in the United States and affects morphology · Synapse · Idiopathic autism models boys 4.5 times more often than girls [68]. Behavioral interventions produce signifcant results in some cases, Abbreviations with early diagnosis being critical for better prognosis [7, ASD Autism spectrum disorders 268]. No cure is currently available and current pharma- PFC Prefrontal cortex cological treatments do not address the core ASD behav- FG Fusiform gyrus iors, but target comorbid conditions such as seizures, CA1 Cornu ammonis 1 anxiety, depression, and attention defcit hyperactivity GABA γ-Aminobutyric acid disorder (reviewed in [88, 125]). VEN von Economo neuron Despite increased research efforts, the pathogenesis FI Frontoinsular of ASD is not fully understood. ASD without a known ACC Anterior cingulate cortex specifc cause is referred to as idiopathic ASD and con- aMCC Anterior midcingulate cortex stitutes the majority of cases. Various environmental PCC Posterior cingulate cortex factors have been proposed that contribute to idiopathic PIOTG Postero-inferior occipitotemporal gyrus ASD, such as maternal immune activation and prenatal CNVs Copy number variations exposure to toxins. Among the known genetic causes of NLGN Neuroligins ASD are de novo mutations identifed in approximately MRI Magnetic resonance imaging 20–30% of cases [81, 286]. The genetic abnormalities KO Knockout associated with ASD may be grouped into three classes: KI Knock-in (1) at least 5% are caused by single gene mutations, PSD Postsynaptic density such as those found in SHANK3, FMR1, or MECP2; (2) AMPA α-Amino-3-hydroxyl-5-methyl-4-isoxazole- approximately 10% are copy number variations (CNVs) propionic acid including duplications, large deletions, inversions, and NMDA N-Methyl-D-aspartic acid translocations of chromosomes, and (3) many are poly- NRXN Neurexins genic risk factors due to accumulation of common vari- WT Wild type ants, each contributing to a portion of the risk. Recent CNTNAP2 Contactin associated protein-like 2 advances in genetic techniques, especially whole-exome SHANK SH3 and multiple ankyrin repeat domains sequencing applied to large cohorts, have uncovered protein forms of genetic variation contributing to risk and ena- MECP2 Methyl-CpG-binding protein 2 bled the identifcation of additional risk genes [83, 165, FMR1 Fragile X mental retardation 1 166, 254, 261, 309]. FMRP Fragile X mental retardation protein A recent prospective magnetic resonance imaging UBE3A E6AP-E3 ubiquitin protein ligase (MRI) study found that early enlargement of cortical sur- TSC Tuberous sclerosis face area between 6 and 12 months of age could predict mTOR Mammalian target of rapamycin for ASD diagnosis in infants, and that the rate of volume CHD8 Chromodomain helicase DNA-binding pro- change in the second year correlates with ASD severity tein 8 [151]. Functional neuroimaging studies have been cru- SCN2A Sodium channel, voltage-gated, type II alpha cial for highlighting the presence of altered activation subunit patterns in specifc brain regions of patients with ASD, SYNGAP1 Synaptic GTPase activating protein 1 such as those involved in emotional regulation and social ARID1B AT-rich interactive domain containing protein interaction (for reviews, see [241, 320]). However, given 1B the technical limitations of neuroimaging studies, such GRIN2B Glutamate receptor ionotropic, NMDA 2B as low spatial resolution and the need for higher func- DSCAM Down syndrome cell adhesion molecule tioning individuals as subjects, these studies need to be TBR1 T-brain-1 complemented by other approaches. Two complementary VPA Sodium valproate approaches address the limited resolution of neuroimag- MIA Maternal immune activation ing studies to detect changes at the cellular level. First, 1 3 Acta Neuropathol neuropathologic explorations in human postmortem tis- most signifcant contributions to the understanding of sue allow for investigation at the cellular and cytoarchi- ASD neuronal and synaptic pathology using mouse tectural levels from individuals with ASD across the models genetically modifed or derived through manip- spectrum. Second, the use of genetic manipulations to ulation of their environment. Finally, to highlight pos- create ASD model organisms enables the identifcation of sible strategies to overcome some of the limitations of molecular pathways central to the pathogenesis of ASD. both research approaches, we discuss the current views The consistent presence of changes in the cerebellum on the interplay between neuropathology and disease revealed by neuropathologic investigations in ASD [35, mechanisms. 385, 386] and the identifcation of synaptic dysfunction in ASD based on studies of mouse models constitute suc- cessful examples of each of these approaches [39]. Neuropathology of ASD: recent fndings In the frst part of the review,
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