Autism Spectrum Disorders

Agenda

*Presentation times are subject to change.

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.

Travel & Lodging

Our Location

The New York Academy of Sciences

7 World Trade Center
250 Greenwich Street, 40th floor
New York, NY 10007-2157
212.298.8600

Click here for directions.

Hotels Near 7 World Trade Center

Recommended partner hotel:

The New York Academy of Sciences is a part of the Club Quarters network. Please feel free to make accommodations with Club Quarters on-line to save significantly on hotel costs.

Club Quarters Reservation Password: NYAS

Club Quarters, World Trade Center
140 Washington Street
New York, NY 10006
Phone: (212) 577-1133

Located on the south side of the World Trade Center, opposite Memorial Plaza, Club Quarters, 140 Washington Street, is just a short walk to our location.

Other hotels located near 7 WTC: