Le volume 224 du périodique Advances in Anatomy, Embryology and Cell Biology est consacré à l’autisme :

Translational Anatomy and Cell Biology of Autism Spectrum Disorder

1. Kleijer KTE, Huguet G, Tastet J, Bourgeron T, Burbach JPH. Anatomy and Cell Biology of Autism Spectrum Disorder : Lessons from Human Genetics. Adv Anat Embryol Cell Biol ;2017 ;224:1-25.

Until recently autism spectrum disorder (ASD) was regarded as a neurodevelopmental condition with unknown causes and pathogenesis. In the footsteps of the revolution of genome technologies and genetics, and with its high degree of heritability, ASD became the first neuropsychiatric disorder for which clues towards molecular and cellular pathogenesis were uncovered by genetic identification of susceptibility genes. Currently several hundreds of risk genes have been assigned, with a recurrence below 1% in the ASD population. The multitude and diversity of known ASD genes has extended the clinical notion that ASD comprises very heterogeneous conditions ranging from severe intellectual disabilities to mild high-functioning forms. The results of genetics have allowed to pinpoint a limited number of cellular and molecular processes likely involved in ASD including protein synthesis, signal transduction, transcription/chromatin remodelling and synaptic function all playing an essential role in the regulation of synaptic homeostasis during brain development. In this context, we highlight the role of protein synthesis as a key process in ASD pathogenesis as it might be central in synaptic deregulation and a potential target for intervention. These current insights should lead to a rational design of interventions in molecular and cellular pathways of ASD pathogenesis that may be applied to affected individuals in the future.

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2. Ecker C, Schmeisser MJ, Loth E, Murphy DG. Neuroanatomy and Neuropathology of Autism Spectrum Disorder in Humans. Adv Anat Embryol Cell Biol ;2017 ;224:27-48.

Autism spectrum disorder (ASD) is a lifelong heterogeneous neurodevelopmental condition that is associated with differences in brain anatomy and connectivity. Yet, the molecular and cellular mechanisms that underpin the atypical developmental of the brain in ASD remain poorly understood. Here, we review the findings of in vivo neuroimaging studies examining the time course of atypical brain development in ASD and relate the different neurodevelopmental stages that are atypical in ASD to the known neurobiological mechanisms that drive the maturation of the typically developing brain. In particular, we focus on the notion of ‘early brain overgrowth’ in ASD, which may lead to differences in the formation of the brain’s micro- and macro-circuitry. Moreover, we attempt to link the in vivo reports describing differences in brain anatomy and connectivity on the macroscopic level to the increasing number of post-mortem studies examining the neural architecture of the brain in ASD on the microscopic level. In addition, we discuss future directions and outstanding questions in this particular field of research and highlight the need for establishing the link between micro- and macro-pathology in the same set of individuals with ASD based on advances in genetic, molecular and imaging techniques. In combination, these may proof to be invaluable for patient stratification and the development of novel pharmacotherapies in the future.

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3. Kathuria A, Sala C, Verpelli C, Price J. Modelling Autistic Neurons with Induced Pluripotent Stem Cells. Adv Anat Embryol Cell Biol ;2017 ;224:49-64.

Autism spectrum disorder (ASD) is a neurodevelopmental condition that affects more than 1% of children per current estimates. It has been characterised by the following two core behavioural phenotypes : (1) deficits in social interaction and communication and (2) repetitive behaviours, restricted interests and activities. Due to the complex nature of ASD, there are currently no effective treatments. The reason behind this is the clinical and genetic heterogeneity between affected individuals on the one hand and the lack of understanding of the underpinning pathophysiological mechanisms on the other hand. Induced pluripotent stem cells (iPSCs) are reprogrammed stem cells from adult cells. These have the capacity to self-renew and differentiate into any type of cells in the body. Therefore, human iPSCs provide a unique opportunity to study the human cellular and molecular phenotypes associated with ASD. Here, we systematically review various ASD variants and co-morbid diseases modelled using human iPSCs.

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4. Molenhuis RT, Bruining H, Kas MJ. Modelling Autistic Features in Mice Using Quantitative Genetic Approaches. Adv Anat Embryol Cell Biol ;2017 ;224:65-84.

Animal studies provide a unique opportunity to study the consequences of genetic variants at the behavioural level. Human studies have identified hundreds of risk genes for autism spectrum disorder (ASD) that can lead to understanding on how genetic variation contributes to individual differences in social interaction and stereotyped behaviour in people with ASD. To develop rational therapeutic interventions, systematic animal model studies are needed to understand the relationships between genetic variation, pathogenic processes and the expression of autistic behaviours. Genetic and non-genetic animal model strategies are here reviewed in their propensity to study the underpinnings of behavioural trait variation. We conclude that an integration of reverse and forward genetic approaches may be essential to unravel the neurobiological mechanisms underlying ASD.

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5. Ferhat AT, Halbedl S, Schmeisser MJ, Kas MJ, Bourgeron T, Ey E. Behavioural Phenotypes and Neural Circuit Dysfunctions in Mouse Models of Autism Spectrum Disorder. Adv Anat Embryol Cell Biol ;2017 ;224:85-101.

Autism spectrum disorder (ASD) is a neurodevelopmental condition primarily characterised by alterations in social interaction and communication combined with the presence of restricted interests and stereotyped behaviours. Mutations in several genes have been associated with ASD resulting in the generation of corresponding mouse models. Here, we focus on the behavioural (social and stereotyped behaviours), functional and structural traits of mice with mutations in genes encoding defined synaptic proteins including adhesion proteins, scaffolding proteins and subunits of channels and receptors. A meta-analysis on ASD mouse models shows that they can be divided into two subgroups. Cluster I gathered models highly impaired in social interest, stereotyped behaviours, synaptic physiology and protein composition, while Cluster II regrouped much less impaired models, with typical social interactions. This distribution was not related to gene families. Even within the large panel of mouse models carrying mutations in Shank3, the number of mutated isoforms was not related to the severity of the phenotype. Our study points that the majority of structural or functional analyses were performed in the hippocampus. However, to robustly link the structural and functional impairments with the behavioural deficits observed, brain structures forming relevant nodes in networks involved in social and stereotyped behaviours should be targeted in the future. In addition, the characterisation of core ASD-like behaviours needs to be more detailed using new approaches quantifying the variations in social motivation, recognition and stereotyped behaviours.

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6. Peter S, De Zeeuw CI, Boeckers TM, Schmeisser MJ. Cerebellar and Striatal Pathologies in Mouse Models of Autism Spectrum Disorder. Adv Anat Embryol Cell Biol ;2017 ;224:103-119.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a strong genetic component. To date, several hundred different genetic mutations have been identified to play a role in its aetiology. The heterogeneity of genetic abnormalities combined with the different brain regions where aberrations are found makes the search for causative mechanisms a daunting task. Even within a limited number of brain regions, a myriad of different neural circuit dysfunctions may lead to ASD. Here, we review mouse models that incorporate mutations of ASD risk genes causing pathologies in the cerebellum and striatum and highlight the vulnerability of related circuit dysfunctions within these brain regions in ASD pathophysiology.

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7. Reim D, Schmeisser MJ. Neurotrophic Factors in Mouse Models of Autism Spectrum Disorder : Focus on BDNF and IGF-1. Adv Anat Embryol Cell Biol ;2017 ;224:121-134.

Neurotrophic factors are secreted proteins promoting the development and maintaining the function of neural circuits. Studies in human individuals with autism spectrum disorder (ASD) and corresponding animal models have implicated that alterations of neurotrophic factor levels and the associated signalling pathways might contribute to the underlying pathophysiology. As most of this work has investigated the role of brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1) in ASD formation, we focus on these two molecules in this review. We start with reviewing findings on neurotrophic factor levels in human individuals with ASD, continue with providing a broad overview on murine BDNF and IGF-1 in several well-established mouse models of ASD and finally discuss the therapeutic potential of both molecules in the context of translational ASD research.

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8. Zhang R, Xu XJ, Zhang HF, Han SP, Han JS. The Role of the Oxytocin/Arginine Vasopressin System in Animal Models of Autism Spectrum Disorder. Adv Anat Embryol Cell Biol ;2017 ;224:135-158.

The nonapeptides oxytocin (OXT) and arginine vasopressin (AVP) are two key mediators in regulating various aspects of mammalian social behaviours. There are several lines of evidence that genetic variants of the OXT/AVP system exist in autism spectrum disorder (ASD) and that this system is dysfunctional at least in some ASD entities. These findings have stimulated the interest to perform studies testing the potential therapeutic application of OXT/AVP in ASD. In this respect animal models are critical for investigating the pathophysiology and for compound screening leading to new therapeutic approaches. Based on findings in animal models that show alterations of the OXT/AVP system, it has been hypothesised that single- or multiple-dose administration or the stimulation of endogenous release can improve several social deficits. Here we comprehensively review the role of the OXT/AVP system in social recognition, social interaction and maternal behaviour in the light of different ASD animal models and patient studies. We further discuss implications for OXT/AVP-related pharmacological interventions to alleviate social deficits in ASD in the future.

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9. Hill-Yardin EL, McKeown SJ, Novarino G, Grabrucker AM. Extracerebral Dysfunction in Animal Models of Autism Spectrum Disorder. Adv Anat Embryol Cell Biol ;2017 ;224:159-187.

Genetic factors might be largely responsible for the development of autism spectrum disorder (ASD) that alone or in combination with specific environmental risk factors trigger the pathology. Multiple mutations identified in ASD patients that impair synaptic function in the central nervous system are well studied in animal models. How these mutations might interact with other risk factors is not fully understood though. Additionally, how systems outside of the brain are altered in the context of ASD is an emerging area of research. Extracerebral influences on the physiology could begin in utero and contribute to changes in the brain and in the development of other body systems and further lead to epigenetic changes. Therefore, multiple recent studies have aimed at elucidating the role of gene-environment interactions in ASD. Here we provide an overview on the extracerebral systems that might play an important associative role in ASD and review evidence regarding the potential roles of inflammation, trace metals, metabolism, genetic susceptibility, enteric nervous system function and the microbiota of the gastrointestinal (GI) tract on the development of endophenotypes in animal models of ASD. By influencing environmental conditions, it might be possible to reduce or limit the severity of ASD pathology.

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10. Schroeder JC, Deliu E, Novarino G, Schmeisser MJ. Genetic and Pharmacological Reversibility of Phenotypes in Mouse Models of Autism Spectrum Disorder. Adv Anat Embryol Cell Biol ;2017 ;224:189-211.

As autism spectrum disorder (ASD) is largely regarded as a neurodevelopmental condition, long-time consensus was that its hallmark features are irreversible. However, several studies from recent years using defined mouse models of ASD have provided clear evidence that in mice neurobiological and behavioural alterations can be ameliorated or even reversed by genetic restoration or pharmacological treatment either before or after symptom onset. Here, we review findings on genetic and pharmacological reversibility of phenotypes in mouse models of ASD. Our review should give a comprehensive overview on both aspects and encourage future studies to better understand the underlying molecular mechanisms that might be translatable from animals to humans.

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