Towards Defining the Pathophysiology of Autistic Behavior (Z4) 2010

Autism is a neurodevelopmental disorder defined by the co-occurrence of a set of characteristic behavioral features. One of the most common neurodevelopmental disorders, autism is recognized as heterogeneous in etiology, phenotype, behavioral trajectory and response to treatment. While the etiology and specific pathogenetic mechanisms underlying autism are unknown, those mechanisms which underlie a small subset of etiologically-defined neurodevelopmental disorders (e.g., Fragile X Syndrome, tuberous sclerosis), that are associated with autism and autistic behaviors, have been well described. The overarching aim of this Keystone Symposia meeting will be to take advantage of our knowledge of etiologic heterogeneity by examining the phenomenology and pathophysiology of etiologically-defined autistic syndromes, and contrasting this with what is known about idiopathic autism, in order to ultimately shape the development of treatment approaches informed by knowledge of the underlying pathophysiology. This conference will bring together clinical and basic scientists from various disciplines to expand on the success of an earlier Keystone Symposia meeting on this topic by additionally: 1) covering a broader number of etiologically-defined autistic syndromes; 2) comparing and contrasting the phenomenology (including physical features, behavior and neural circuitry) of autistic syndromes, to refine ideas regarding etiologically-meaningful aspects of the autism phenotype; 3) examining the role of the environment (epigenetic influences) in contributing to the etiology and underlying mechanisms of autism (including idiopathic autism and autistic syndromes), with the aim of elucidating a more comprehensive understanding of the pathophysiology of autistic behavior; and 4) examining how gene-by-environment (GxE) factors impact synaptic function and plasticity that may lie at the heart of autism syndromes. Goals: 1. Define more precisely the common and unique clinical features of syndromic and idiopathic autism. The field needs a realistic view of autism heterogeneity with regard to phenotype expression, longitudinal course and diversity in response to treatment. What are key differences in the social and communication domains between individuals with Rett, Fragile X, Angelman Syndromes compared to idiopathic autisms? To what extent is the heterogeneity in single gene disorders similar or different than in idiopathic autisms, for example, in relation to mental health issues? 2. Provide novel insight into the role of complex genetic mechanisms in autism. To what extent do we understand how different genetic etiologies (CNVs, syndromic disorders common variants) contribute to the autism? Can we better understand the role of specific genetic modifiers that result in expression of the core clinical and other symptoms in distinct syndromic and idiopathic autism? 3. Provide a basic understanding of and define the roles for epigenetics in understanding the causes of the autism. How are specific gene X environment interactions relevant to the study of the autisms? How can studies of cancer and other common diseases inform those working on the autisms regarding the roles of gene modification in the disorder process? Are there ways in which clinical and basic studies can integrate efforts to define epistatic and epigenetic factors in the autisms? 4. Examine the common cellular mechanisms that underlie the autisms. Re-examine the disconnection-synapse hypothesis of the autisms through a new perspective of factors that influence synapse formation and maturation. Is the synapse most vulnerable in most brain disorders in general due to the magnitude of the molecular machinery that goes into making, breaking and stabilizing synapses?