Understanding Autism: From Basic Neuroscience to Treatment PDF

Preface

This volume presents a comprehensive review of the state-of-the-art research on the diagnosis, treatment, and prevention of autism. It also addresses potential mechanisms that may underlie the development of autism and the neural systems that are likely to be affected by these molecular, genetic, and infectious etiologies.

Autism is a devastating neurodevelopmental disorder with early childhood onset and a recently reported prevalence of as high as 73 per 10,000. Autistic symptoms continue throughout life and include significant impairments in social, communicative, cognitive, and behavioral functioning. There is strong evidence for genetic factors in the etiology of autism; however, the mode of inheritance is complex and reflects the interplay of the environment and many different genetic factors.

Postmortem and MRI studies have identified abnormalities in several major cortical and subcortical brain structures in autism, and neuropsychological studies have implicated specific impairments in executive functioning and in processing social and emotional information. Distinctive neuropathological features have been reported, such as Purkinje cell loss in the cerebellum. Recent work has implicated neonatal brain undergrowth followed by rapid and excessive postnatal brain growth. Whereas these studies are consistent with the hypothesis that autism is primarily a disorder of brain functioning, no defining set of pathophysiological mechanisms has been unambiguously defined. Animal models offer a complementary approach to human studies and provide the opportunity to study in an experimental system the neural substrates of behaviors that are profoundly impaired in autistic individuals. One particularly promising avenue of inquiry has focused on the neurobiology of social behavior. Despite promising results, researchers have yet to identify a robust model of many of the core abnormalities observed in autism and their specific neurodevelopmental trajectories. This may be a limitation of studying nonhumans.

The past few years have witnessed extraordinary advances in molecular genetic techniques and the accumulation of structural genomics information and resources in both human and model organisms (Moldin and Hyman, 2005). In addition, new approaches are dramatically increasing our understanding of brain development, structure, and function. With the development of new technologies and the availability of genomic resources, previously inconceivable experiments in basic neuroscience are now being routinely implemented in autism research.

Research activities are being stimulated by funding from private foundations including Cure Autism Now, the National Alliance for Autism Research, the Southwest Autism Research and Resource Center, the Simons Foundation, and Autism Speaks - and multiple institutes at the National Institutes of Health (NIMH, NINDS, NICHD, NIDCD, NIEHS). Intensive autism advocacy interest resulted in the creation of the Coalition for Autism Research and Education (CARE), formed by members of the Congressional Autism Caucus, which includes nearly 200 congressmen from almost every state. The Children's Health Act of 2000 passed by Congress mandated the establishment of autism research centers and an Interagency Autism Coordinating Committee (IACC) to coordinate autism research and other efforts within the Department of Health and Human Services. Members include the five NIH institutes that support autism research and numerous other federal agencies, e.g., CMS, CDC, DOE, FDA, and HRSA.

The availability of exciting new scientific tools and technologies, as well as intensive advocacy efforts and the availability of millions of dollars in funding from private foundations, are setting the stage for a renaissance in autism research studies in humans and in experimental systems. These burgeoning research activities will have a profound impact on generating considerable insights into the etiology and pathophysiology of autism. However, much of the current research on autism has not achieved its full potential, as human studies, guided by a fundamental grounding in neural pathways, circuits, and molecules, expand continuously with the avalanche of information being made available with the sequencing of the human genome and those of other organisms (Moldin, 2003).

This volume reviews key findings on autism, ranging from the genetic and neural mechanisms that may underlie this disorder through state-of-the-art diagnosis, epidemiology, clinical neuroscience, and treatment approaches. The book concludes with a chapter that discusses the economic cost of autism and provides a biomedical and public health perspective of the impact of this devastating disease. The chapters are authored by clinical and basic researchers who are at the forefront of molecular and systems neuroscience, clinical neuroscience, genetics, and health economics.

The first section (Chapter 1 and Chapter 2) describes current approaches to diagnosis of autism and autism spectrum disorders, and reviews the state of the art of the epidemiology of autism. The latter is especially important, given the recent controversies about the changing incidence and prevalence of autism.

The second section (Chapter 3 to Chapter 6) covers genetic and genomic technologies that are currently being used to dissect the molecular basis of autism. Chapter 3 provides an exhaustive review of cytogenetic, linkage, association, candidate gene, and genetic mapping studies in autism. Chapter 4 describes exciting new approaches to the analysis of gene expression and also the extension of current studies to include endophenotypes in families of autistic probands. Chapter 5 examines the potential role that epigenetic mechanisms may play in the etiology of autism, through the regulation of gene expression by mechanisms that do not alter gene sequences.

The analysis of specific developmental disorders that result in autistic symptoms are providing insights into mechanisms underlying autism. These include Angelman's and Rett syndromes (Chapter 5), tuberous sclerosis, and Fragile X syndrome (Chapter 6). Fragile X syndrome is caused by reduced expression of the FMRP RNA-binding protein whose function is linked to synaptic function. Based on observations made in Fragile X and several other lines of evidence, the field is currently exploring the possibility that alterations in synapse development and signaling may underlie some forms of autism (Zogbi, 2003; Rubenstein and Merzenich, 2003; Levitt et al., 2004). This perspective has been bolstered by the identification of function-altering mutations in some neuroligin genes in a small subset of autistic people (Jamain et al., 2003). Neuroligin proteins, together with their binding partners (neurexins), regulate the formation of synapses; different neurexin/neuroligin combinations appear to participate in specifying whether new synapses are assembled into excitatory or inhibitory synapses (Graf et al., 2004; Chih et al., 2005; Chubykin et al., 2005; Cline, 2005).

Given that ~40% of autistic people develop epilepsy, a syndrome characterized by excessive excitatory tone, it is possible that autism can be caused by developmental abnormalities that alter the ratio of excitatory/inhibitory synapses in key neural circuits (Hussman, 2001; Rubenstein and Merzenich, 2003; Levitt et al., 2004). This hypothesis is currently being examined in several laboratories. For instance, Rett syndrome results in increased expression of the Dlx5 transcription factor (Horike et al., 2005). The Dlx gene family has a central role in regulating the development and function of forebrain inhibitory neurons (Panganiban and Rubenstein, 2002; Cobos et al., 2005). Recently, five nonsynonymous Dlx2 and Dlx5 mutations have been identified in autistic probands (Hamilton et al., 2005). Although it is premature to conclude that there is a causal link that connects the Rett gene (MeCP2), the Dlx genes, and autism, this line of investigation illustrates one current approach that is aimed at elucidating the molecular and cellular basis for some forms of autism.

The third section of this volume (Chapter 7 to Chapter 13) focuses on behaviors, and the neural systems that underlie them, that are frequently abnormal in autistic people. These include fear and anxiety (Chapter 7), cerebellar networks (Chapter 8), language (Chapter 9), the prefrontal cortex (Chapter 10), the amygdala and other aspects of complex social behavior (Chapter 11), and the thalamus and neuromodulatory systems (Chapter 12). All of these chapters are especially important to neuroscientists and nonneuroscientists alike, given that they provide a clear explication of the molecular and cellular neuroscience of autism that serve as the bedrock for future autism research paradigms. Chapter 13 describes the considerable potential of animal models in autism for characterizing the roles of genes and environment, understanding pathogenesis, and testing potential therapeutic approaches. This approach is important, given the recent controversies regarding the potential link between autism and environmental neurotoxins, such as mercury.

The fourth section (Chapter 14 to Chapter 17) describes current clinical findings from studies of autistic people. Included are reviews and perspectives that focus on neuroanatomy and neurochemistry (Chapter 14), functional neuroimaging (Chapter 15), structural neuroimaging (Chapter 16), and neurophysiology and neuropsychology (Chapter 17). Given well-replicated observations of elevated platelet serotonin in a subset of autistic probands and first-degree relatives (Chapter 14), considerable excitement has been generated by recent work (McCauley et al., 2004; Sutcliffe et al., 2005) implicating multiple rare alleles at the serotonin transporter locus ( SLC6A4 ) in the etiology of autism.

Current state-of-the-art treatments for autism are described in the fifth section. The discussion of both pharmacological (Chapter 18) and behavioral, educational, and developmental treatments (Chapter 19) point to new avenues for future research, and also suggest ways in which our understanding of underlying neural systems can inform drug development and therapeutics.

Finally, this volume concludes with discussion of the health economics of autism (Chapter 20) that includes a theoretical and methodological outline of how to identify the public health costs of autism. Also included are estimates of those costs based on publicly available data. In any given year, autism can cost our society about $3.2 million per autistic child; over a lifetime each individual costs a staggering $35 billion in direct medical, direct non-medical, and lost productivity costs to care for all autistic children over all of their lifetimes. Ganz's work is the most comprehensive cost analysis conducted to date, and this information will be useful to cost-effectiveness analysts performing economic evaluations of treatment and prevention options and to policymakers and advocates as a reference source on the costs of autism.

We anticipate that this book will be a valuable resource for clinical and basic scientists, as well as legislators and research advocates, and will provide a powerful and comprehensive synthesis of current research on autism and its underlying neural substrates. This information is expected to grow and guide future basic and clinical research on autism. A key objective is to stimulate new directions for research on etiology and pathophysiology, as well as for the development of new drugs.

We express our appreciation to each of the contributors who worked so diligently on their chapters, and the anonymous reviewers who generously took the time to carefully read each chapter and provide detailed feedback to the authors. Steven Moldin is grateful for all of the kind encouragement and support he received from Yelizaveta Zolotukhina. We also thank the staff of CRC Press/Taylor and Francis Group, especially Barbara Norwitz and Kari Budyk, for their help, patience, and encouragement.

Most importantly, we express our deep gratitude to the caring relatives of autistic people, to the health care workers and researchers who dedicate themselves to this serious problem, and to the advocates who vigorously raise funds, raise public awareness, and fight for legislation aimed at solving this difficult problem. Their devotion to the scientific pursuit of greater understanding, better treatments - and ultimately a cure - has been an inspiration to us. It is to them, and to the people with autism whom we wish to help, that we humbly dedicate this book.