Autism Spectrum Disorders

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Autism Spectrum Disorders

Tuesday, April 26, 2011

The New York Academy of Sciences

Autism spectrum disorders are neurodevelopmental syndromes that affect up to 1% of the population.  There are no effective treatments for the core diagnostic symptoms of impaired social interactions, communication deficits, repetitive behaviors, and restricted interests.  In this symposium, we will explore and discuss emerging areas of research that are laying the foundation for development of novel therapeutics to treat Autism Spectrum Disorders.

This event will also be broadcast as a webinar.

Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City, where possible.

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Agenda

*Presentation times are subject to change.


9:00 AM

Introduction
Daniel G. Smith, PhD, Pfizer

9:10 AM

The Role of Synaptic Cell-Adhesion Pathways in the Pathogenesis of Autism Spectrum Disorders
Joseph Buxbaum, PhD, Mount Sinai School of Medicine

10:05 AM

Oxytocin and the Experimental Therapeutics of Autism
Eric Hollander, MD, Albert Einstein College of Medicine and Montefiore Medical Center

11:00 AM

Coffee Break

11:30 AM

Neuroimaging Approaches to Biomarker Development for Autism Research
Robert Schultz, PhD, University of Pennsylvania/Children’s Hospital of Philadelphia

12:25 PM

Lunch Break

1:10 PM

MEG Imaging and Auditory-Gating in Autism Patients: a Potential Biomarker
Timothy Roberts, PhD, Children's Hospital, University of Pennsylvania

2:05 PM

Behavioral Phenotyping Strategies for Genetic Mouse Models of Autism
Jacki Crawley, PhD, National Institute of Mental Health, NIH

3:00 PM

Coffee Break

3:30 PM

Modeling mTOR Signalopathies in Autism
Peter Crino, MD, PhD, University of Pennsylvania/Children's Hospital of Philadelphia

4:25 PM

Panel Discussion
All speakers, moderated by Robert H. Ring, PhD, Pfizer

5:00 PM

Networking Reception

Organizers

Robert H. Ring, PhD

Pfizer

Daniel G. Smith, PhD

Pfizer

Mercedes E. A. Beyna, MS

Pfizer

Jennifer S. Henry, PhD 

The New York Academy of Sciences

Speakers

Joseph D. Buxbaum, PhD

Mount Sinai School of Medicine

Joseph D. Buxbaum, PhD is the G. Harold and Leila Y. Mathers Professor of Psychiatry, Neuroscience, and Genetic and Genomic Sciences, and the Head of The Laboratory of Molecular Neuropsychiatry at Mount Sinai. Dr. Buxbaum is the Director of the Seaver Autism Center, and his research focuses on using techniques of molecular genetics and molecular neuroscience to identify, and ultimately characterize, genes that contribute to autism susceptibility. His laboratory has identified common and rare genetic variants that underlie autism and autism spectrum disorders and has developed model systems in which novel therapeutics can be tested. In addition, Dr. Buxbaum has taken a lead in several international consortia dedicated to advancing research in autism spectrum disorders. Dr. Buxbaum is co-editor-in-chief of the journal Molecular Autism

Jacqueline N. Crawley, PhD

National Institute of Mental Health, NIH

Dr. Crawley is Chief of the Laboratory of Behavioral Neuroscience of the Intramural Research Program, National Institute of Mental Health, NIH in Bethesda, Maryland. She received a B.A. in Biology from the University of Pennsylvania in 1971, Ph.D. in Zoology from the University of Maryland in 1976, and conducted postdoctoral research in neuropsychopharmacology at Yale University School of Medicine. She is an Adjunct Professor at Georgetown University and the recipient of numerous honors and awards, including AAAS Fellow, NARSAD Council member, President of the International Behavioral Neuroscience Society, President of the International Behavioural and Neural Genetics Society, Mathilde Solowey Lecture Award in Neuroscience, Howard Hughes Medical Research Institute Preceptor Award, Society for Neuroscience Membership Committee Chairmanship Award, Fleur Strand Summer Neuropeptide Conference Award, International Behavioral Neuroscience Society Marjorie A. Myers Lifetime Achievement Award, Albany Autism Awareness Day Keynote Award, and IMFAR 2010 Plenary Lecturer. She serves as Editor-in-Chief of the journal Neuropeptides and on the editorial boards of twelve scientific journals. Dr. Crawley authored the widely-used book What′s Wrong With My Mouse? Behavioral Phenotyping of Transgenic and Knockout Mice. Her research team developed a three-tiered strategy for mouse behavioral phenotyping, which has been applied to investigate mutant mouse models of Alzheimer's, anxiety, Ataxia Telangiectasia, attention deficit hyperactivity disorder, autism, cognitive decline, depression, epilepsy, Fragile X syndrome, , Lowe syndrome, Phelan-McDermid syndrome, Sandhoff’s, schizophrenia, Smith-Lemli-Opitz syndrome, and Tay-Sachs.

Currently Dr. Crawley’s research program focuses on behavioral phenotyping of mouse models of autism. Behavioral assays relevant to the diagnostic and associated behavioral symptoms of autism have been assembled by her team, to investigate the functional readouts of mice with mutations in genes associated with autism. Focus has been on synaptic proteins, including receptors, transporters, and cell adhesion proteins including neuroligins and shanks. Forward genetics approaches with inbred strains of mice have identified the BTBR T+tf/J strain which incorporates social abnormalities, communication deficits, and repetitive behaviors. Behavioral interventions and drug treatments that rescue autism-relevant behaviors in BTBR are leading to discoveries of potential treatments to reduce the symptoms of autism spectrum disorders.

Peter B. Crino, MD, PhD

University of Pennsylvania

Dr. Crino received his M.D. from Yale and his Ph.D. in Neuroscience from Boston University. He completed neurology residency training and a Howard Hughes Medical Institute post-doctoral fellowship in molecular biology at the University of Pennsylvania. He is currently Associate Professor in the Department of Neurology and Director of the epilepsy program at Penn. Dr. Crino maintains an NIH funded research program focused on developmental brain malformations associated with epilepsy and autism.

Eric Hollander, MD

Montefiore Medical Center, Albert Einstein College of Medicine

Dr. Hollander is Director of the Compulsive, Impulsive and Autism Spectrum Disorders Program, and Clinical Professor of Psychiatry and Behavioral Sciences at the Albert Einstein College of Medicine and the Montefiore Medical Center University Hospital Albert Einstein College of Medicine. Formerly, he has served as the Esther and Joseph Klingenstein Professor and Chairman of Psychiatry, Director of the Seaver and Greater NY Autism Center of Excellence, and Director of the Compulsive, Impulsive and Anxiety Disorders Program at Mount Sinai School of Medicine. Prior to then, he was Associate Professor of Psychiatry and Director of the Compulsive and Impulsive Disorders Program at Columbia University College of Physicians and Surgeons.

Dr. Hollander has served as the principal investigator for a number of federal grants, including the NIH Greater New York Autism Center of Excellence, the NIMH Research Training Grant in Psychopharmacology and Outcomes Research, and an FDA funded multicenter treatment trial of pediatric body dysmorphic disorder. He was the principal investigator of the autism Clinical Trials Network, and Chair of the eight centers NIH STAART Autism Steering Committee. He is involved in research on the neuropharmacology, neuropsychiatry, functional imaging, and treatment of obsessive-compulsive disorder, impulsive/aggressive personality disorders, obsessive-compulsive-related disorders such as body dysmorphic disorder, pathological gambling, and autism. Dr. Hollander has received a Research Scientist Development Award from the National Institute of Mental health to investigate the psychobiology of obsessive-compulsive and related disorders. He has received orphan drug grants from the Food and Drug Administration to study new treatments for body dysmorphic disorder, child/adolescent autism, and adult autism, and a grant from the National Institute of Drug Abuse for a study on the neurobiology of pathological gambling. He has received several grants from the National Institute of Mental Health, and the National Institute of Neurological Disorders and Stroke, to develop treatments for borderline personality disorder, adolescent body dysmorphic disorder, and autism. Dr. Hollander has received two national research awards from the American Psychiatric Association and a Distinguished Investigator Award from the National Alliance for Research in Schizophrenia and Depression. During his career, Dr. Hollander has published more than 500 scientific reports in the psychiatric field. He has edited 19 books, including the American Psychiatric Publishing Textbook of Autism Spectrum Disorders (2011).

Timothy T. Roberts, PhD

Children's Hospital of Philadelphia

Timothy P.L. Roberts, PhD obtained his doctorate from Cambridge University, England in 1992. He has subsequently been on the faculty at UCSF and the University of Toronto and is presently holder of the Oberkircher Family Chair in Pediatric Radiology and Vice-Chair for Research in the Department of Radiology at Children's Hospital of Philadelphia as well as Professor of Radiology, University of Pennsylvania. His work in 4D functional imaging using biomagnetic recording as well as advanced MRI techniques (such as diffusion tensor imaging), specifically in the study of auditory processing and language has been supported by the National Alliance for Autism Research and is presently supported, by Autism-Speaks, the Nancy Lurie Marks Family Foundation, the Commonwealth of Pennsylvania and NlH.  He has published in excess of 200 scientific papers, mostly in the field of physiologic and functional imaging, reviews grant proposals for NIH (standing member, DBD) and several equivalent international agencies (UK, Germany, Austria, Singapore, lsrael, Cyprus, Canada, Holland), and serves on the executive committee of the American Society for Neuroradiology, the American Society for Functional
Neuroradiology (President 2009-10) and the lnternational Society for the Advancement of Clinical MEG (President 2009-1 1).

Robert T. Schultz, PhD

Children's Hospital of Philadelphia

Robert T. Schultz, Ph.D., received his PhD in Psychology in 1991 from the University of Texas at Austin, receiving training in psychopathology, neuropsychology and behavioral genetics. He received postdoctoral training in cognitive neuroscience at Yale University, and joined the faculty there in 1994, where he rose to be the Harris Associate Professor of Child Psychology and Psychiatry. In 2007 he moved to Children’s Hospital of Philadelphia, and became the Director of a new center – the Center for Autism Research (CAR). He is also the RAC Endowed Professor of Psychology in the Department of Pediatrics at the University of Pennsylvania School of Medicine. He is the recent past President of the International Society for Autism Research, and has served as the Associate Editor of the society’s journal, Autism Research. His research interests are broad, and include the relationships between genes, brain, behavior and treatment in autism. He is best known for his work with functional MRI to study the social brain in autism, and for his interest in social perception, and the development of novel computer based gaming approaches to treating these social deficits.

Sponsors

For sponsorship opportunities please contact Carmen McCaffery at cmccaffery@nyas.org or 212.298.8642.

Academy Friend

Novartis Institutes for BioMedical Research

Roche

Grant Support

This event is funded in part by the Life Technologies™ Foundation.

Podcast Sponsor

Autism Speaks

Promotional Partners

Antibodies Online GmbH

NeuroDevNet

The Dana Foundation

Abstracts

The Role of Synaptic Cell-Adhesion Pathways in the Pathogenesis of Autism Spectrum Disorders

Joseph Buxbaum, PhD, Mount Sinai School of Medicine

Recently, rare variants of major effect have been identified in multiple neurodevelopmental disorders, including autism and associated conditions. This in turn has provided an opportunity to develop model systems that have strong construct validity for such disorders. Model systems, most frequently genetically modified mice, are in turn providing insights into the molecular and cellular pathophysiology of neurodevelopmental disorders, and are defining therapeutic targets for these disorders. In the example of Fragile X syndrome, mouse and other models with a disruption in the Fmr1 gene have led to clinical trials reducing glutamate transmission and/or signaling via the metabotropic glutamate receptor. Our own work on Shank3-deficient mice indicates that enhancing glutamate transmission could be beneficial in cases of autism spectrum disorders. Altogether, genetic findings are providing important new avenues for therapeutics in autism and associated conditions

Oxytocin and the Experimental Therapeutics of Autism

Eric Hollander, MD Albert Einstein College of Medicine and Montefiore Medical Center

Animal studies have helped to define the role of oxytocin in social recognition, pair bonding, social cognition, social memory, and stereotypic behaviors. Studies in healthy volunteers, children and adults with autism, and adults with related conditions such as social anxiety disorder, schizophrenia and borderline personality disorder, have further elucidated the role of the oxytocin system in modulating core symptom domains of autism. Drug delivery methods, outcome measures, biomarkers, and stratification strategies are critical issues in developiong experimental therapeutic approaches to autism based on modulation of the oxytocin system. Current findings, future directions and novel approaches to drug development will be highlighted.

Neuroimaging Approaches to Biomarker Development for Autism Research

Robert T. Schultz, PhD, Children’s Hospital of Philadelphia

The autism spectrum disorders (ASD) are a heterogeneous group of related disorders with a very strong genetic basis. ASD appears to be like cerebral palsy or intellectual disability, for which there may be dozens or perhaps even hundreds of different causes with an overlapping but not identical impact on the developing brain. The similarity of the impact produces the similarity of outward manifestations; the differences between causes produce the wide spectrum of disability. ASD heterogeneity has complicated the search for causes and effective treatments. Reliable behavioral signatures and biomarkers are needed to help make sense of this heterogeneity. Although defined by a triad of deficits, much work in the fields of experimental cognitive psychology and cognitive neuroscience has focused on the social deficits, which are often accorded a special role in causal models of ASD. This presentation will review cognitive and neuroimaging data on social functioning in ASD, focusing on paradigms and approaches that have been shown across studies to have the greatest promise for serving as reliable endophenotypes of ASD. Characterizing and refining behavioral and biomarkers for ASD is a high priority. These markers can be used in programmatic efforts to relate differences in genetic susceptibility factors to differences in brain, behavior and development. Predictive biomarkers in infants during the first year of life would be particularly valuable for identifying those most at risk or ASD before the disorder onsets. In older children, biomarkers could be used to predict who will respond best to which treatment, and as a measure of treatment response. This presentation will review promising candidate brain and behavioral markers for ASD, with a focus on the social brain.

Electrophysiological Signatures of Language lmpairment in Autism Spectrum Disorders

Timothy Roberts, PhD, The Children's Hospital of Philadelphia

Language impairment is a core aspect of the autism phenotype, present in a significant fraction, but not all children with diagnoses of autism spectrum disorders. Abnormal auditory processing has been suggested as a neural underpinning of such impairment. MEG determination of evoked response tatencies to (i) simple isolated tones, and (ii) oddball (mismatch) paradigms of differing tones and/or vowels can be used to index successive stages of auditory processing. Separately, diffusion tensor magnetic resonance imaging (DTl) can be used to probe the integrity of white matter tracts of the auditory pathway (in particular the aeoustic radiations). Approximately 100 children (age 6-1Syears; -40 typically develofing; - 60 autism spectrum disorder) underwent successful MEG recording and DTI study. All data were recorded on a 27S-channel biomagnetometer (VSM MedTech). MRI was conducted at 3T using a Siemens VerioTM system and a diffusion weighted imaging seguence with 30 non-collinear encoding
directions and 2mm isotropic spatial resolution. Clinical determination of language impairment was assessed behaviorally using the Clinical Evaluation of Language Fundamentals-lV (CELF4) test, using a threshold standardized score of <85 to indicate impairment.

Main findings of this study are: (1) delayed M100 response latencies (-10-20ms) in children with ASD compared to typically-developing peers; this delay does not distinguish children with autism spectrum disorders with and without concomitant language impairment (CELF-4 < or > 85). (2) Delayed "normalization" of M100 latency with developmentalage in children with ASD compared to typically developing peers - M100 latency continues to shorten with age in both groups, but at a significantly slower rate in ASD. The age-mediated M100 latency in typicaldevelopment is significantly associated with increasing fractional anisotropy (FA) of the acoustic radiations (interpreted as an index of white matter integrity/maturation). (3) MMF latencies are significantly prolonged in children with ASD, but this effect is especially pronounced in children with ASD with concomitant language impairment (-50ms). An age-covaried mixed-model with hemisphere (2), tone(2) and group(3) found a main effect of diagnostic group, with pair-wise comparisons all significant (p<0.05) indicating resolution of ASD with language impairment from ASD without language impairment and from typical development. Electrophysiological measures of auditory processing at various stages may offer diagnostic insight with early responses discriminating ASD per se, and later responses showing resolution of language impairment sub-groups.

Behavioral Phenotyping Strategies for Genetic Mouse Models of Autism

Jacqueline N. Crawley, PhD, National Institute of Mental Health, NIH

Autism is a major mental illness with a strong genetic component. As candidate genes linked to autism are identified, mice with targeted mutations of these genes are becoming available. Model organisms offer useful translational tools to test hypotheses about single genes, chromosomal locus deletions, copy number variants, methylation and other epigenetic mechanisms, neuroanatomical abnormalities, environmental toxins, diets, immune dysfunctions, and other proposed causes of autism. The key to translational applications is robust, highly replicable functional assays. Our laboratory and others are developing mouse behavioral paradigms with conceptual analogies to the three diagnostic symptoms of autism. This presentation will focus on behavioral tests for mice that offer reasonable face validity to the defining symptoms of autism. The core deficit in reciprocal social interactions is being modeled longitudinally across developmental stages with juvenile play and automated adult social approach and social interaction tasks. Communication in mice is being approached with measures of the emission, detection, and responses to olfactory and auditory social cues. The third diagnostic criterion of motor stereotypies, repetitive behaviors, insistence on sameness, and narrow restricted interests is being analyzed in mice by quantitating stereotyped motor behaviors, repetitive self-grooming, perseveration during the reversal phase of T-maze and Morris water maze spatial tasks, and restricted exploration of complex environments. Comprehensive control parameters are scored to avoid overinterpretation of artifacts. Behavioral assays relevant to the associated symptoms of autism, including mental retardation, anxiety, seizures, sleep disruption, and hyperreactivity to sensory stimuli, may provide further insights into the phenotypes of a mouse model of autism spectrum disorders.

Both forward genetics and reverse mouse genetics are employed in our laboratory to understand the genetic basis of social, communication, and repetitive behaviors. BTBR T+tf/J, an inbred strain that displays autism-like traits on many of these tasks, will be used to illustrate phenotypes of a robust mouse model of autism. Representative results in mice with targeted mutations in candidate genes for autism will be described. Targeted gene mutations and inbred strains of mice that incorporate traits with face validity to the diagnostic and associated symptoms of autism spectrum disorders offer attractive model systems to evaluate potential treatments. Early preclinical results will be presented on drug treatments and environmental interventions that reverse components of the autism-relevant behavioral phenotypes in the BTBR mouse model of autism.

Epilepsy, Autism, and Brain Malformations: A Spectrum Along the mTOR Cascade

Peter B. Crino, MD, PhD, University of Pennsylvania

Over the past 10 years it has become apparent that there are a group of neuropsychiatric disorders variably characterized by epilepsy, autism, and cognitive disability that are associated with alterations in brain cytoarchitecture. The model disease for this family of disorders is Tuberous Sclerosis Complex (TSC), an autosomal dominant disorder associated with mutations in TSC1 or TSC2, which encode proteins that directly modulate the activity of mammalian target of rapamycin (mTOR). Subsequent analysis has demonstrated that additional subtypes of focal cortical malformations (FCM) known to be associated with intractable epilepsy in children and adults including focal cortical dysplasia (FCD), hemimegalencephaly (HME), and ganglioglioma (GG) are associated with abnormal signaling activation of the mTOR pathway. FCM are the most common cause of intractable epilepsy in children and thus, there remains a clear biomedical and public health relevance to studying these brain disorders. Interestingly, recent evidence suggests that Fragile-X syndrome and autism-macrocephaly syndrome are also linked to mTOR signaling abnormalities via FMR-1 and PTEN, respectively. We recently collaborated in describing a new FCM autosomal recessive syndrome (polyhydramnios, megalencephaly, symptomatic epilepsy syndrome, PMSE), resulting from mutation in STRADα, another known mTOR modulatory protein. Clearly, hyperactivation of mTOR may be central to the pathogenesis of certain subtypes of FCM associated with epilepsy and autism. To capture the essence of the spectrum of these disorders, we coined the tem “mTORopathies” to define a continuum of neurological disorders characterized by altered cortical architecture, abnormal neuronal morphology, altered behavior, and intractable seizures as a consequence of abnormal mTOR signaling.

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