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Clinical and Neurobiological Relevance of Current Animal Models of Autism Spectrum Disorders.

ABSTRACT: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication impairments, as well as repetitive and restrictive behaviors. The phenotypic heterogeneity of ASD has made it overwhelmingly difficult to determine the exact etiology and pathophysiology underlying the core symptoms, which are often accompanied by comorbidities such as hyperactivity, seizures, and sensorimotor abnormalities. To our benefit, the advent of animal models has allowed us to assess and test diverse risk factors of ASD, both genetic and environmental, and measure their contribution to the manifestation of autistic symptoms. At a broader scale, rodent models have helped consolidate molecular pathways and unify the neurophysiological mechanisms underlying each one of the various etiologies. This approach will potentially enable the stratification of ASD into clinical, molecular, and neurophenotypic subgroups, further proving their translational utility. It is henceforth paramount to establish a common ground of mechanistic theories from complementing results in preclinical research. In this review, we cluster the ASD animal models into lesion and genetic models and further classify them based on the corresponding environmental, epigenetic and genetic factors. Finally, we summarize the symptoms and neuropathological highlights for each model and make critical comparisons that elucidate their clinical and neurobiological relevance.

SUBMITTER: Kim KC

PROVIDER: S-EPMC4859786 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Clinical and Neurobiological Relevance of Current Animal Models of Autism Spectrum Disorders.

Kim Ki Chan KC Gonzales Edson Luck EL Lázaro María T MT Choi Chang Soon CS Bahn Geon Ho GH Yoo Hee Jeong HJ Shin Chan Young CY

Biomolecules & therapeutics 20160501 3

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication impairments, as well as repetitive and restrictive behaviors. The phenotypic heterogeneity of ASD has made it overwhelmingly difficult to determine the exact etiology and pathophysiology underlying the core symptoms, which are often accompanied by comorbidities such as hyperactivity, seizures, and sensorimotor abnormalities. To our benefit, the advent of animal models has allowed us to asses ...[more]

PMID: 27133257

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Project description: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.

Project description:Multiple lines of evidence indicate a strong genetic contribution to autism spectrum disorders (ASDs). Current guidelines for clinical genetic testing recommend a G-banded karyotype to detect chromosomal abnormalities and fragile X DNA testing, but guidelines for chromosomal microarray analysis have not been established.A cohort of 933 patients received clinical genetic testing for a diagnosis of ASD between January 2006 and December 2008. Clinical genetic testing included G-banded karyotype, fragile X testing, and chromosomal microarray (CMA) to test for submicroscopic genomic deletions and duplications. Diagnostic yield of clinically significant genetic changes was compared.Karyotype yielded abnormal results in 19 of 852 patients (2.23% [95% confidence interval (CI): 1.73%-2.73%]), fragile X testing was abnormal in 4 of 861 (0.46% [95% CI: 0.36%-0.56%]), and CMA identified deletions or duplications in 154 of 848 patients (18.2% [95% CI: 14.76%-21.64%]). CMA results for 59 of 848 patients (7.0% [95% CI: 5.5%-8.5%]) were considered abnormal, which includes variants associated with known genomic disorders or variants of possible significance. CMA results were normal in 10 of 852 patients (1.2%) with abnormal karyotype due to balanced rearrangements or unidentified marker chromosome. CMA with whole-genome coverage and CMA with targeted genomic regions detected clinically relevant copy-number changes in 7.3% (51 of 697) and 5.3% (8 of 151) of patients, respectively, both higher than karyotype. With the exception of recurrent deletion and duplication of chromosome 16p11.2 and 15q13.2q13.3, most copy-number changes were unique or identified in only a small subset of patients.CMA had the highest detection rate among clinically available genetic tests for patients with ASD. Interpretation of microarray data is complicated by the presence of both novel and recurrent copy-number variants of unknown significance. Despite these limitations, CMA should be considered as part of the initial diagnostic evaluation of patients with ASD.

Project description:Fragile X syndrome and tuberous sclerosis are genetic syndromes that both have a high rate of co-morbidity with autism spectrum disorders. Several lines of evidences suggest that these two monogenic disorders may converge at a molecular level through the dysfunction of activity-dependent synaptic plasticity. We utilized mouse models of these monogenic disorders to identify genome-wide transcriptional changes in cerebellum and blood and characterize the (dis-)similarity of their molecular signatures. Differentially expressed genes and enriched pathways were distinct for the two mouse models examined, with the exception of immune system related pathways. In the cerebellum of the Fmr1 knockout (Fmr1-KO) model, the neuroactive ligand receptor interaction pathway and gene sets associated with synaptic plasticity such as long term potentiation, gap junction, and axon guidance were the most significantly perturbed pathways. The phosphatidylinositol signaling pathway was significantly dysregulated in both blood and brain of Fmr1-KO mice. In both the blood and brain of the Tsc2 heterozygous mouse model, immune system related pathways, genes encoding ribosomal proteins, and glycolipid metabolism pathways were significantly perturbed. Our data suggest that distinct molecular pathways may be involved in autism spectrum disorders with known but different genetic causes, and that blood gene expression profiles of Fmr1-knockout and Tsc2+/- mice mirror some, but not all, of the perturbed molecular pathways in the brain. For the Fmr1-KO model, 10 mice, consisting of 5 KO and 5 WT mice, were profiled. Thus, 10 pairs of blood and cerebella samples were profiled. Likewise, for the Tsc+/- model, 3 transgenic and 3 WT mice were sacrificed and paired blood and cerebella samples were prepared for gene expression profiling. All samples were profiled using the Affymetrix Mouse Gene ST 1.0 ST arrays. Three factors—tissue (i.e. blood vs. cerebellum), treatment (i.e. knockout vs. wildtype), and genetic background (Fmr1-KO vs. Tsc2+/-)—were analyzed with analysis of variance (ANOVA). Subsequently, we compared blood and brain gene expression changes in Fmr1 and Tsc2 knockout mice models using WT littermates as controls using t-tests with unequal variances. The false discovery rate (FDR) was calculated using Storey and Tibshirani’s method.

Project description:The core symptoms and co-morbidities associated with autism spectrum disorders (ASD) affect daily living and quality of life. Existing pharmacological interventions are only able to attenuate some related symptoms but are unable to address the underlying etiologies associated with ASD. Anecdotal evidence, which claims benefit from the use of cannabis to treat symptoms among this population, has been gaining popularity as families seek solutions.This paper analyzed recent peer-reviewed literature to identify the current state of evidence regarding cannabis use for the ASD population. Systematic reviews, reports, and experimental studies were assessed to understand the current extent and nature of the evidence on the risks and benefits of cannabis use for ASD. At this time, three large-scale clinical trials are currently at varying stages of progress and publication of results. Only five small studies were identified that have specifically examined cannabis use in ASD. Given the sparse state of evidence directly assessed in this population, studies which examined effects of cannabis on shared pathological symptoms of ASD such as hyperactivity, sleep disorders, self-injury, anxiety, behavioral problems, and communication were also reviewed.Studies revealed mixed and inconclusive findings of cannabis effects for all conditions, except epilepsy. Adverse outcomes were also reported, which included severe psychosis, increased agitation, somnolence, decreased appetite, and irritability. In addition, a wide range of cannabis compositions and dosage were identified within the studies, which impact generalizability.There is currently insufficient evidence for cannabis use in ASD, which creates an urgent need for additional large-scale controlled studies to increase understanding of risks and benefits and also to examine the impact of "entourage effects." This will support discussions of treatment options between health care providers and ASD patients and their families. Evidence may lead to a desired new line of treatment or prevent adverse outcomes from unsubstantiated use amongst families aiming for symptom reduction.

Dataset Information

Clinical and Neurobiological Relevance of Current Animal Models of Autism Spectrum Disorders.

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Clinical and Neurobiological Relevance of Current Animal Models of Autism Spectrum Disorders.

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