Functional Characterization Of Altered Neurodevelopmental Mechanisms In Autism Using Patient Specific Induced Pluripotent Stem Cells

To date, numerous candidate genes have been associated with autism spectrum disorder (ASD) with many of these genes known to have important roles in synaptic function and the development of neural circuits. This suggests that certain neurobiological processes could be commonly altered in ASD. Therefore, although there is a great deal of clinical and genetic heterogeneity in ASDs, there may be convergent deficits in key molecular mechanisms which underlie the disease. Although this is encouraging, a lack of appropriate human-based models of complex neurodevelopmental disorders has greatly hindered investigations of convergent neurobiology in ASD. Patient-specific induced pluripotent stem cells (iPSCs) can be used to model brain region-specific neuronal development in genetic backgrounds known to result in certain pathological conditions. This ability to model neurodevelopment in vitro permits the characterization of disease mechanisms that manifest themselves during the early steps of brain development in ASD, facilitating the identification of common molecular mechanisms disrupted in this disorder. Importantly, the identification of common pathways in ASD that are disrupted in the early stages of disease development could serve as important candidate targets for therapeutic intervention. Patient-specific iPSC lines were derived from the whole blood of individuals affected with idiopathic ASD, and subsequently differentiated into cortical neurons for up to 135 days in culture. The findings of transcriptome and gene network analysis indicate that iPSC-derived neurons from our cohort of ASD individuals have altered expression of genes associated with synaptic function, Wnt signaling, neuronal differentiation, and various processes involving the extracellular matrix (i.e. axon guidance and cell migration). Furthermore, our data show that genes previously implicated in ASD and intellectual disability are significantly overrepresented in gene coexpression networks related to synaptic function that are transcriptionally co-regulated by Wnt. Finally, we demonstrate that neurons derived from our sample cohort of idiopathic ASD individuals have excessive neurite outgrowth at an early stage of cortical neurogenesis. In sum, our data indicate that convergent molecular disturbances in ASD impact synaptic development and function, metabolism, and cellular molecular interactions involving the extracellular matrix. Furthermore, our results from transcriptome and gene-network analysis both indicate considerable transcriptional dysregulation during earlier stages of neuronal development.

In the years following publication of the DSM-5(R), the field of psychiatry has seen vigorous debate between the DSM's more traditional, diagnosis-oriented approach and the NIMH's more biological, dimension-based RDoC (research domain criteria) approach. Charney & Nestler's Neurobiology of Mental Illness is an authoritative foundation for translating information from the laboratory to clinical treatment, and its fifth edition extends beyond this reference function to acknowledge and examine the controversies, different camps, and thoughts on the future of psychiatric diagnosis. In this wider context, this book provides information from numerous levels of analysis, including molecular biology and genetics, cellular physiology, neuroanatomy, neuropharmacology, epidemiology, and behavior. Sections and chapters are edited and authored by experts at the top of their fields. No other book distills the basic science and underpinnings of mental disorders-and highlights practical clinical significance-to the scope and breadth of this classic text. In this edition, Section 1, which reviews the methods used to examine the biological basis of mental illness in animal and cell models and in humans, has been expanded to reflect critically important technical advances in complex genetics (including powerful sequencing technologies and related bioinformatics), epigenetics, stem cell biology, optogenetics, neural circuit functioning, cognitive neuroscience, and brain imaging. This range of established and emerging methodologies offer groundbreaking advances in our ability to study the brain as well as unique opportunities for the translation of preclinical and clinical research into badly needed breakthroughs in our therapeutic toolkit. Sections 2 through 7 cover the neurobiology and genetics of major psychiatric disorders: psychoses (including bipolar disorder), mood disorders, anxiety disorders, substance use disorders, dementias, and disorders of childhood onset. Also covered within these sections is a summary of current therapeutic approaches for these illnesses as well as the ways in which research advances are now guiding the search for new treatments. Each of these parts has been augmented in several different areas as a reflection of research progress. The last section, Section 8, reconfigured in this new edition, now focuses on diagnostic schemes for mental illness. This includes an overview of the unique challenges that remain in diagnosing these disorders given our still limited knowledge of disease etiology and pathophysiology. The section then provides reviews of DSM-5(R), which forms the basis of psychiatric diagnosis in the United States for all clinical work, and of RDoC, which provides an alternative perspective on diagnosis in heavy use in the research community. Also included are chapters on future efforts toward precision and computational psychiatry, which promise to someday align diagnosis with underlying biological abnormalities.

This Research Topic has the aim to fill the gap of the many unresolved scientific issues on Autism Spectrum Disorders (ASD) that are still in need of investigation, Targeted treatments based on the understanding of the underlying pathogenic mechanisms of disease are still lacking. Further research is awaited and should be obtained through a significant effort on experimental treatment trials and neuroscience research. This Topic is divided in two main sections, one covering clinical issues and another on basic neurosciences of Autism Spectrum Disorders. A more detailed description of the contents of the articles is provided in the editorial at the beginning of the issue.

This volume provides an introduction to the essential techniques required for studying the molecular biology of brain disease. The approaches and strategies for investigations of gene structure and regulation are described with reference to the molecular genetics of prion and Alzheimer's disease. The effects of aberrant gene regulation can also be examined at the protein level by immunocytochemistry and autoradiography. Improved understanding of basic biology has resulted in new approaches to animal models using transgenic techniques and new therapeutic approaches. The volume is structured to illustrate all these approaches and demonstrate the practice and promise of molecular neuropathology.

The International Workingmen’s Association was the prototype of all organizations of the Labour movement and the 150th anniversary of its birth (1864-2014) offers an important opportunity to rediscover its history and learn from its legacy. The International helped workers to grasp that the emancipation of labour could not be won in a single country but was a global objective. It also spread an awareness in their ranks that they had to achieve the goal themselves, through their own capacity for organization, rather than by delegating it to some other force; and that it was essential to overcome the capitalist system itself, since improvements within it, though necessary to pursue, would not eliminate exploitation and social injustice. This book reconsider the main issues broached or advanced by the International – such as labor rights, critiques of capitalism and the search for international solidarity – in light of present-day concerns. With the recent crisis of capitalism, that has sharpened more than before the division between capital and labour, the political legacy of the organization founded in London in 1864 has regained profound relevance, and its lessons are today more timely than ever. This book was published as a special issue of Socialism and Democracy.

Since 1975, Dr. Kenneth Swaiman’s classic text has been the reference of choice for authoritative guidance in pediatric neurology, and the 6th Edition continues this tradition of excellence with thorough revisions that bring you fully up to date with all that’s new in the field. Five new sections, 62 new chapters, 4 new editors, and a reconfigured format make this a comprehensive and clearly-written resource for the experienced clinician as well as the physician-in-training. Nearly 3,000 line drawings, photographs, tables, and boxes highlight the text, clarify key concepts, and make it easy to find information quickly. New content includes 12 new epilepsy chapters, 5 new cerebrovascular chapters, and 13 new neurooncology chapters, as well as new chapters on neuroimmunology and neuromuscular disorders, as well as chapters focused on clinical care (e.g., Counseling Families, Practice Guidelines, Transitional Care, Personalized Medicine, Special Educational Law, Outcome Measurements, Neurorehabilitation, Impact of Computer Resources, and Training Issues). Additional new chapters cover topics related to the developmental connectome, stem cell transplantation, and cellular and animal models of neurological disease. Greatly expanded sections to increase your knowledge of perinatal acquired and congenital disorders, neurodevelopmental disabilities, pediatric epilepsy, and nonepileptiform paroxysmal disorders and disorders of sleep. Coverage of new, emerging, or controversial topics includes developmental encephalopathies, non-verbal learning disorders, and the pharmacological and future genetic treatment of neurodevelopmental disabilities.

This book discusses the primary functions of microtubule-associated proteins (MAPs) such as MAP2 and tau in neuronal morphogenesis, as well as relationships between neuronal differentiation and the expression of neuronal intermediate filaments (nestin, alpha internexin, and neurofilament triplet proteins). It emphasizes the importance of several cytoskeletal proteins for neuronal differentiation and morphogenesis, organelle transport, and synaptic functions. The book considers the involvement of tau MAPs in the formation of paired helical filaments in Alzheimer's disease, and it examines the mechanisms of organelle transports and molecular motors such as kinesin, braindynein, and kinesin superfamily proteins. Cytoskeletal proteins involved in synaptic formation and transmitter release and new synaptic junctional-associated proteins are explored as well.