La revue Progress in Brain Research propose un numéro spécial sur les modèles génétiques en jeu dans les TSA :

Genetic Models and Molecular Pathways Underlying Autism Spectrum Disorders

1. Patel J, Lukkes JL, Shekhar A. Chapter 1 – Overview of genetic models of autism spectrum disorders. Progress in brain research. 2018 ; 241 : 1-36.

Autism spectrum disorders (ASDs) are a group of neurodevelopment disorders that are characterized by heterogenous cognitive deficits and genetic factors. As more ASD risk genes are identified, genetic animal models have been developed to parse out the underlying neurobiological mechanisms of ASD. In this review, we discuss a subset of genetic models of ASD, focusing on those that have been widely studied and strongly linked to ASD. We focus our discussion of these models in the context of the theories and potential mechanisms of ASD, including disruptions in cell growth and proliferation, spine dynamics, synaptic transmission, excitation/inhibition balance, intracellular signaling, neuroinflammation, and behavior. In addition to ASD pathophysiology, we examine the limitations and challenges that genetic models pose for the study of ASD biology. We end with a review of innovative techniques and concepts of ASD pathology that can be further applied to and studied using genetic ASD models.

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2. Molosh AI, Shekhar A. Chapter 2 – Neurofibromatosis type 1 as a model system to study molecular mechanisms of autism spectrum disorder symptoms. Progress in brain research. 2018 ; 241 : 37-62.

Neurofibromatosis type 1 (NF1) is monogenic neurodevelopmental disorder caused by mutation of NF1 gene, which leads to increased susceptibility to various tumors formations. Additionally, majority of patients with NF1 are experience high incidence of cognitive deficits. Particularly, we review the growing number of reports demonstrated a higher incidence of autism spectrum disorder (ASD) in individuals with NF1. In this review we also discuss face validity of preclinical Nf1 mouse models. Then we describe discoveries from these animal models that have uncovered the deficiencies in the regulation of Ras and other intracellular pathways as critical mechanisms underlying the Nf1 cognitive problems. We also summarize and interpret recent preclinical and clinical studies that point toward potential pharmacological therapies for NF1 patients.

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3. Vithayathil J, Pucilowska J, Landreth GE. Chapter 3 – ERK/MAPK signaling and autism spectrum disorders. Progress in brain research. 2018 ; 241 : 63-112.

The MAPK pathway is a prominent intracellular signaling pathway regulating various intracellular functions. Components of this pathway are mutated in a related collection of congenital syndromes collectively referred to as neuro-cardio-facio-cutaneous syndromes (NCFC) or Rasopathies. Recently, it has been appreciated that these disorders are associated with autism spectrum disorders (ASD). In addition, idiopathic ASD has also implicated the MAPK signaling cascade as a common pathway that is affected by many of the genetic variants that have been found to be linked to ASDs. This chapter describes the components of the MAPK pathway and how it is regulated. Furthermore, this chapter will highlight the various functions of the MAPK pathway during both embryonic development of the central nervous system (CNS) and its roles in neuronal physiology and ultimately, behavior. Finally, we will summarize the perturbations to MAPK signaling in various models of autism spectrum disorders and Rasopathies to highlight how dysregulation of this pivotal pathway may contribute to the pathogenesis of autism.

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4. Drozd HP, Karathanasis SF, Molosh AI, Lukkes JL, Clapp DW, Shekhar A. Chapter 4 – From bedside to bench and back : Translating ASD models. Progress in brain research. 2018 ; 241 : 113-58.

Autism spectrum disorders (ASD) represent a heterogeneous group of disorders defined by deficits in social interaction/communication and restricted interests, behaviors, or activities. Models of ASD, developed based on clinical data and observations, are used in basic science, the “bench,” to better understand the pathophysiology of ASD and provide therapeutic options for patients in the clinic, the “bedside.” Translational medicine creates a bridge between the bench and bedside that allows for clinical and basic science discoveries to challenge one another to improve the opportunities to bring novel therapies to patients. From the clinical side, biomarker work is expanding our understanding of possible mechanisms of ASD through measures of behavior, genetics, imaging modalities, and serum markers. These biomarkers could help to subclassify patients with ASD in order to better target treatments to a more homogeneous groups of patients most likely to respond to a candidate therapy. In turn, basic science has been responding to developments in clinical evaluation by improving bench models to mechanistically and phenotypically recapitulate the ASD phenotypes observed in clinic. While genetic models are identifying novel therapeutics targets at the bench, the clinical efforts are making progress by defining better outcome measures that are most representative of meaningful patient responses. In this review, we discuss some of these challenges in translational research in ASD and strategies for the bench and bedside to bridge the gap to achieve better benefits to patients.

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5. Garg S, Green J. Chapter 5 – Studying child development in genetic models of ASD. Progress in brain research. 2018 ; 241 : 159-92.

This chapter approaches the early development in autism spectrum disorder (ASD) through comparative study of some key monogenic syndromic models of ASD in humans. Using this method, as well as referring to relevant work in idiopathic ASD, we address three complimentary areas : (i) patterns of ASD behavioral phenotype expression across genetic syndromes, as a way of addressing gene-phenotype correlations ; (ii) longitudinal developmental trajectories toward autism in early childhood, as a way of addressing developmental specificity ; and (iii) experimental intervention trials, for treatment and mechanism discovery. The comparative approach does not highlight striking phenotypic specificity, but early studies were often limited and more methodologically sophisticated recent studies may suggest subtle distinctions. Longitudinal studies are at an early stage but can build on the substantive work on early prodromal development of idiopathic ASD. Translational intervention trials to date have not found candidate treatments and we argue that a new generation of more ambitious experimental mechanism trials is needed. This field now has the opportunity to combine comparative prospective longitudinal developmental studies with in-depth cross-syndrome phenotyping and linked ambitious targeted mechanistic interventions in a way that could be mutually informing and maximize the potential of syndromic models to illuminate the pathophysiology of ASD.

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6. Walsh KS, Rau S. Chapter 6 – Measurement considerations in pediatric research on autism spectrum disorders. Progress in brain research. 2018 ; 241 : 193-220.

Studying Autism Spectrum Disorders (ASD) in genetic syndromes has gained interest in the scientific community as a way to elucidate mechanisms and symptom profiles to understand ASD more broadly. Appropriate and adequate measurement of constructs, symptomatology, and outcomes in clinical research is of vital importance in establishing the prevalence of such symptoms and measuring change in symptoms in the context of clinical trials. As such, we provide an overview of the prevalence of ASD, present current diagnostic guidelines, discuss important comorbidities to consider, describe current assessment strategies in assessing ASD, and discuss these within the context of a specific genetic condition to highlight how ASD can be best evaluated.

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7. Shekhar A. Preface. Progress in brain research. 2018 ; 241 : xi.

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