Progress in Molecular Biology and Translational Science : Autism (Juillet 2020)

dimanche 2 août 2020

La série monographique Molecular Biology and Translational Science propose en juillet 20202 un volume consacré au TSA.

1. Steinman G. The putative etiology and prevention of autism. Prog Mol Biol Transl Sci ;2020 ;173:1-34.

Since the initial psychological report by Leo Kanner in 1943, relatively little formal biochemical/neurological research on the cause of autism, other than peripheral searches for genomic mutations, had been carried until the end of the 20th century. As a result of studies on twin sets and the conclusion that autism was largely a hereditary defect, numerous investigations have sought various genetic faults in particular. However, such studies were able to reveal a plausible etiology for this malady in only a small percentage of instances. Key bio-molecular characteristics of this syndrome have been uncovered when the potential roles of the glia were studied in depth. Findings related to biochemical deficiencies appearing early in the newborn, such as depressed IGF-1 (insulin-like growth factor #1) in neurogenesis/myelination, are becoming emphasized in many laboratories. Progress leading to timely diagnoses and subsequent prevention of central nervous system dysconnectivity now seems plausible. The tendency for an infant to develop autism may currently be determinable and preventable before irreversible psychosocial disturbances become established. These discussions about glial function will be inter-spersed with comments about their apparent relevance to autism. The concluding portion of this presentation will be a detailed review and summation of this diagnosis and prevention proposition.

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2. Saxena R, Babadi M, Namvarhaghighi H, Roullet FI. Role of environmental factors and epigenetics in autism spectrum disorders. Prog Mol Biol Transl Sci ;2020 ;173:35-60.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder thought to be caused by predisposing high-risk genes that may be altered during the early development by environmental factors. The impact of maternal challenges during pregnancy on the prevalence of ASD has been widely studied in clinical and animal studies. Here, we review some clinical and pre-clinical evidence that links environmental factors (i.e., infection, air pollution, pesticides, valproic acid and folic acid) and the risk of ASD. Additionally, certain prenatal environmental challenges such as the valproate and folate prenatal exposures allow us to study mechanisms possibly linked to the etiology of ASD, for instance the epigenetic processes. These mechanistic pathways are also presented and discussed in this chapter.

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3. Park DI. Genomics, transcriptomics, proteomics and big data analysis in the discovery of new diagnostic markers and targets for therapy development. Progress in Molecular Biology and Translational Science ;2020 ;173:61-90.

Highly complex endophenotypes and underlying molecular mechanisms have prevented effective diagnosis and treatment of autism spectrum disorder. Despite extensive studies to identify relevant biosignatures, no biomarker and therapeutic targets are available in the current clinical practice. While our current knowledge is still largely incomplete, -omics technology and machine learning-based big data analysis have provided novel insights on the etiology of autism spectrum disorders, elucidating systemic impairments that can be translated into biomarker and therapy target candidates. However, more integrated and sophisticated approaches are vital to realize molecular stratification and individualized treatment strategy. Ultimately, systemic approaches based on -omics and big data analysis will significantly contribute to more effective biomarker and therapy development for autism spectrum disorder.

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4. Geng X, Kang X, Wong PCM. Autism spectrum disorder risk prediction : A systematic review of behavioral and neural investigations. Prog Mol Biol Transl Sci ;2020 ;173:91-137.

A reliable diagnosis of autism spectrum disorder (ASD) is difficult to make until after toddlerhood. Detection in an earlier age enables early intervention, which is typically more effective. Recent studies of the development of brain and behavior in infants and toddlers have provided important insights in the diagnosis of autism. This extensive review focuses on published studies of predicting the diagnosis of autism during infancy and toddlerhood younger than 3 years using behavioral and neuroimaging approaches. After screening a total of 782 papers, 17 neuroimaging and 43 behavioral studies were reviewed. The features for prediction consist of behavioral measures using screening tools, observational and experimental methods, brain volumetric measures, and neural functional activation and connectivity patterns. The classification approaches include logistic regression, linear discriminant function, decision trees, support vector machine, and deep learning based methods. Prediction performance has large variance across different studies. For behavioral studies, the sensitivity varies from 20% to 100%, and specificity ranges from 48% to 100%. The accuracy rates range from 61% to 94% in neuroimaging studies. Possible factors contributing to this inconsistency may be partially due to the heterogeneity of ASD, different targeted populations (i.e., high-risk group for ASD and general population), age when the features were collected, and validation procedures. The translation to clinical practice requires extensive further research including external validation with large sample size and optimized feature selection. The use of multi-modal features, e.g., combination of neuroimaging and behavior, is worth further investigation to improve the prediction accuracy.

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5. Leung MK, Lau WK. Resting-state abnormalities of posterior cingulate in autism spectrum disorder. Prog Mol Biol Transl Sci ;2020 ;173:139-159.

The posterior cingulate cortex (PCC) plays pivotal roles in cognitive, social and emotional processing, as well as early neural development that supports complex interactions among different neural networks. Alterations in its local and long-range connectivity during resting state are often implicated in neuropathology of neurodevelopmental disorders such as autism spectrum disorder (ASD). ASD is characterized by social and communication deficits, as well as restricted and repetitive behaviors and interests. Individuals with ASD demonstrate persistent disturbances in cognitive and social-emotional functioning, and their PCC exhibits both local and long-range resting state abnormalities compared to typically developing healthy controls. In terms of regional metrics, only the dorsal part of the PCC showed local underconnectivity. As to long-range connectivity measures, the most replicated finding in ASD studies is the reduced functional coupling between the PCC and medial prefrontal cortex (MPFC), which may represent a core neuropathology of ASD unrelated to medication effects. Functional importance of these resting state abnormalities to ASD and directions of future study are discussed at the end of this chapter.

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6. Cheung PPP, Lau BWM. Neurobiology of sensory processing in autism spectrum disorder. Prog Mol Biol Transl Sci ;2020 ;173:161-181.

Altered sensory processing and perception has been one of the characteristics of autism spectrum disorder (ASD). In this chapter, we review the neural underpinnings of sensory abnormalities of ASD by examining the literature on clinical, behavioral and neurobiological evidence that underlies the main patterns of sensory integration function and dysfunction. Furthermore, neural differences in anatomy, function and connectivity of different regions underlying sensory processing are also discussed. We conclude that sensory integration intervention is built on the premise of neuroplasticity to improve function and behavior for individuals with ASD.

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7. Pietropaolo S, Bellocchio L, Bouzón-Arnáiz I, Yee BK. The role of the endocannabinoid system in autism spectrum disorders : Evidence from mouse studies. Prog Mol Biol Transl Sci ;2020 ;173:183-208.

A substantive volume of research on autism spectrum disorder (ASD) has emerged in recent years adding to our understanding of the etiopathological process. Preclinical models in mice and rats have been highly instrumental in modeling and dissecting the contributions of a multitude of known genetic and environmental risk factors. However, the translation of preclinical data into suitable drug targets must overcome three critical hurdles : (i) ASD comprises a highly heterogeneous group of conditions that can markedly differ in terms of their clinical presentation and symptoms, (ii) the plethora of genetic and environmental risk factors suggests a complex, non-unitary, etiopathology, and (iii) the lack of consensus over the myriad of preclinical models, with respect to both construct validity and face validity. Against this backdrop, this Chapter traces how the endocannabinoid system (ECS) has emerged as a promising target for intervention with predictive validity. Recent supportive preclinical evidence is summarized, especially studies in mice demonstrating the emergence of ASD-like behaviors following diverse genetic or pharmacological manipulations targeting the ECS. The critical relevance of ECS to the complex pathogenesis of ASD is underscored by its multiple roles in modulating neuronal functions and shaping brain development. Finally, we argue that important lessons have been learned from the novel mouse models of ASD, which not only stimulate game-changing innovative treatments but also foster a consensual framework to integrate the diverse approaches applied in the search of novel treatments for ASD.

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8. Baker E, Stavropoulos KKM. The effects of oxytocin administration on individuals with ASD : Neuroimaging and behavioral evidence. Prog Mol Biol Transl Sci ;2020 ;173:209-238.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by difficulties in social communication and the presence of restricted interests and repetitive behaviors. Although behavioral interventions are numerous, there are no Federal Drug Administration approved pharmacological treatments for the core symptoms of ASD. The neuropeptide oxytocin has been studied in animals for decades, and is involved in pair bonding and social affiliation. Given oxytocin’s involvement in social communication in animals, researchers have begun exploring whether oxytocin administration in humans affects social behaviors and attachment. Particular attention has been paid to whether oxytocin has therapeutic benefits for improving social behaviors in individuals with ASD. Research on oxytocin administration in ASD has utilized both behavioral and brain-based outcomes. This chapter reviews the effects of oxytocin administration in ASD, with a focus on functional outcomes from neuroimaging investigations. Evidence of potential therapeutic benefits are reviewed, as well as limitations of extant research. A proposed model for future research into the therapeutic benefits of oxytocin includes combining pharmacological (e.g. oxytocin) and behavioral (e.g. evidence-based behavioral interventions) techniques to improve social communication skills in ASD.

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9. Andoh M, Ikegaya Y, Koyama R. Microglia in animal models of autism spectrum disorders. Prog Mol Biol Transl Sci ;2020 ;173:239-273.

Various genetic and environmental factors have been suggested to cause autism spectrum disorders (ASDs). A variety of animal models of ASDs have been developed and used to investigate the mechanisms underlying the pathogenesis of ASDs. These animal models have contributed to clarifying that abnormalities in neuronal morphology and neurotransmission are responsible for the onset of ASDs. In recent years, researchers have started to focus not only on neurons but also on glial cells, particularly microglia. This is because microglial malfunction is strongly associated with structural and functional abnormalities of neurons, as well as the inflammation that is commonly observed both in the brains of patients with ASDs and in animal models of ASDs. In this chapter, we first introduce a list of commonly available animal models of ASDs and describe the validity of each model from the viewpoint of behaviors and neuroanatomy. We next detail the malfunction of microglia that has been reported in animal models of ASDs and discuss the roles of microglia in ASD pathogenesis. We will further propose possible therapeutic strategies to tackle ASDs by controlling microglial functions.

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10. Chen O, Tahmazian I, Ferrara HJ, Hu B, Chomiak T. The early overgrowth theory of autism spectrum disorder : Insight into convergent mechanisms from valproic acid exposure and translational models. Prog Mol Biol Transl Sci ;2020 ;173:275-300.

The development of new approaches for the clinical management of autism spectrum disorder (ASD) can only be realized through a better understanding of the neurobiological changes associated with ASD. One strategy for gaining deeper insight into the neurobiological mechanisms associated with ASD is to identify converging pathogenic processes associated with human idiopathic clinicopathology that are conserved in translational models of ASD. In this chapter, we first present the early overgrowth theory of ASD. Second, we introduce valproic acid (VPA), one of the most robust and well-known environmental risk factors associated with ASD, and we summarize the rapidly growing body of animal research literature using VPA as an ASD translational model. Lastly, we will detail the mechanisms of action of VPA and its impact on functional neural systems, as well as discuss future research directions that could have a lasting impact on the field.

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11. Scuderi C, Verkhratsky A. The role of neuroglia in autism spectrum disorders. Prog Mol Biol Transl Sci ;2020 ;173:301-330.

Neuroglia are a large class of neural cells of ectodermal (astroglia, oligodendroglia, and peripheral glial cells) and mesodermal (microglia) origin. Neuroglial cells provide homeostatic support, protection, and defense to the nervous tissue. Pathological potential of neuroglia has been acknowledged since their discovery. Research of the recent decade has shown the key role of all classes of glial cells in autism spectrum disorders (ASD), although molecular mechanisms defining glial contribution to ASD are yet to be fully characterized. This narrative conceptualizes recent findings of the broader roles of glial cells, including their active participation in the control of cerebral environment and regulation of synaptic development and scaling, highlighting their putative involvement in the etiopathogenesis of ASD.

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12. Thorsen M. Oxidative stress, metabolic and mitochondrial abnormalities associated with autism spectrum disorder. Prog Mol Biol Transl Sci ;2020 ;173:331-354.

Autism spectrum disorder is a neurodevelopmental disorder characterized by impaired development and by abnormal function in regards to social interaction, communication and restricted, repetitive behavior. It affects approximately 1% of the worldwide population. Like other psychiatric disorders the diagnosis is based on observation of, and interview with the patient and next of kin, and diagnostic tests. Many genes have been associated with autism, but only few highly penetrant. Some researchers have instead focused on oxidative stress, metabolic abnormalities and mitochondrial dysfunction as an explanation of the disorder. Currently no cure exists for the disorder, making these abnormalities interesting as they are possibly correctable with supplements or treatment. These various processes cannot be seen independently as they are influencing and interacting with each other. Furthermore many of the metabolic changes seen in autism have also been shown in other psychiatric disorders such as attention deficit hyperactivity disorder, schizophrenia and bipolar disorder along with often comorbid disorders like epilepsy and intellectual disability. As such some of these abnormalities are not specific, however, could indicate a similar mechanism for the development of these disorders, with symptomatology and severity varying according to the location and the amount of damage done to proteins, cells and DNA. Clinical studies trying to treat these abnormalities, have widely been successful in correcting the metabolic abnormalities seen, but only some studies have also shown bettering of autistic symptoms. Hopefully with increased knowledge of the pathophysiology of the disorder, future preventive measures or treatment can be developed.

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13. Hohmann SS, Ilieva M, Michel TM. In vitro models for ASD-patient-derived iPSCs and cerebral organoids. Prog Mol Biol Transl Sci ;2020 ;173:355-375.

Autism spectrum disorder (ASD) is a set of pervasive neurodevelopmental disorders. The causation is multigenic in most cases, which makes it difficult to model the condition in vitro. Advances in pluripotent stem cell technology has made it possible to generate in vitro models of human brain development. Induced pluripotent stem cells (iPSCs) can be generated from somatic cells and have the ability to differentiate to all of the body’s cells. This chapter aims to give an overview of the iPSC technology for generating neural cells and cerebral organoids as models for neurodevelopment and how these models are utilized in the study of ASD. The combination of iPSC technology and the genetic modification tool CRISPR/Cas9 is described, and current limitations and future perspectives of iPSC technology is discussed.

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