On October 16, 2008, Autism Speaks – together with organizers Isaac Pessah, Ph.D., from the University of California Davis, Pamela Lein, Ph.D., from Oregon State Health Sciences University, and Michael Aschner, Ph.D., from Vanderbilt University – hosted a special day-long symposium at the 25th Annual Neurotoxicology Meeting in Rochester, NY. The symposium was part of a five day conference attended by 200 people that covered such topics as: environmental toxicants, neurodegeneration and neurodevelopment, genetic basis of behavioral neurotoxicity, developmental neurotoxicity, and translational research that focuses on developing models to test new treatments for environmental exposures. Adding to the special nature of the conference, Dr. Bernard Weiss, a pioneer in the field of neurotoxicology, was honored throughout the meeting.

During the session entitled "Animal Models of Autism Spectrum Disorders: Information for Neurotoxicologists," data from eleven scientists, clinicians and researchers was presented for discussion. The goal of the session was to focus research on the integration of environmental exposures and genetic influence in order to encourage toxicologists to develop new models of this complex disorder.

In order to first familiarize researchers new to autism, Susan Hyman, M.D., from the University of Rochester, provided the participants with a thorough overview of the core signs and symptoms of autism, highlighting how autism is diagnosed behaviorally, both through parent and clinical observations, using specific criteria which captures deficits in three areas of functioning. She highlighted symptoms that may be targeted in animal models, and emphasized the need for models to understand the neurobiology of the disorder. This presentation set the stage for how researchers can approach development of autism models for study of toxicological exposure.

David Threadgill, Ph.D., from North Carolina State University, Valerie Bolivar, Ph.D., from the Wadsworth Center in NY, and Flavio Keller, M.D., from the Universito Bio-Medico in Rome all presented information about mouse models of genetic susceptibility to environmental factors. What made these presentations distinct was their different approach to this issue. Dr. Bolivar focused on nine specific mouse strains used in neurobehavioral studies, especially the "BTBR" mouse, which appears to show profound and specific impairments in social interaction. This model will become increasingly relevant to study autism as more specific behavioral assays to investigate social interaction or social preference are developed. Dr. Threadgill represented a collaborative study to develop mouse strains that represent genetic variability in the population. In this way, you can represent a huge range of diversity across the species and be able to link different behaviors to different areas of the genome. Finally, Dr. Keller presented new data on one proposed model of autism genetic susceptibility, the "reelin knockout" mouse. Human studies have implicated this gene in both Alzheimer's Disease and autism, and Dr. Keller's group has advanced the field by studying the interaction of the reelin gene with a commonly used pesticide, chlorpyrifos. Each of these presentations provided a unique perspective to understanding how genetic susceptibility could be used – from population based, to strain differences, to specific gene knockout – to allow researchers to examine the role of environmental factors on these genes.

Other animal models were presented, including a primate model presented by Dr. David Amaral from UC Davis. Work at the MIND Institute has shown that mothers affected with autism sometimes show specific antibody proteins in their blood, and the researchers are studying whether this could contribute to the pathogenesis of autism in their offspring. Dr. Amaral showed videos of primates treated with serum (from mothers of children affected with autism) that contains these antibodies. The offspring showed repetitive, restricted behaviors and low interest in normal primate interaction.

Taking advantage of other, simpler, models, Isaac Pessah, Ph.D. and Pamela Lein, Ph.D. used "in vitro" models that included cell culture and tissue slice models to examine the effects of low levels of toxicant exposure on physiological endpoints such as electrical activity, complexity of neurons, and cell signaling. Dr. Pessah reported on recent work studying the role of the toxicants PCB and PBDE on calcium signaling, and noted that many genes of interest in autism susceptibility act through either response or release of calcium signaling. This suggests a common point of convergence across genes and a future focus of environmental exposure research. Finally, Linda Restifo, Ph.D. from the University of Arizona presented the possibility that the fruit fly Drosophila could be used as an unusual model for toxicant exposure in autism, as its genetics are well known, and she and her colleagues have used this model to explore the effects of environmental exposures on the nervous system.

In addition to calcium signaling, Lisa Opanashuk, Ph.D., from the University of Rochester and Emanuel DiCicco-Bloom, M.D., from the University of Medicine and Dentistry of New Jersey explored how their independently-developed models (one of dioxin exposure, the other using a genetic mutant of the ENGRAILED gene) showed similar defects in cellular function and development, and hypothesized that future "gene x environment" studies combining these two risk factors may show even more serious deficits. Mark Noble, Ph.D., from the University of Rochester, complemented the presentation of Dr. Pessah by explaining how toxicants can change the "oxidative potential" of a cell, and how this can change the function of proteins involved in cell signaling.

Following the presentations, a panel discussion which included Sallie Bernard of SafeMinds and Autism Speaks, Lee Grossman of the Autism Society of America, as well as Patricia Rodier and Troy Zacarone from the University of Rochester. The panel reviewed the importance of these animal models and the role they could play to test many exposures quickly and cheaply (fruit fly, cells, and even mice). It was agreed that the approach needed to be parallel rather than hierarchical, meaning mechanistic studies using lower-order species were essential to better identifying causes and potential treatments. On the other hand, primate and rodent models can provide information on behavioral symptoms that other models can not. The panel and speakers also agreed that epidemiological/treatment studies should not ignore environmental exposures as a cause or environmental interventions as treatments. Treatment response adds an important layer of complexity on "gene x environment" interactions but should continue to be explored vigorously. Novel and innovative approaches to studying genetic and environmental causes of autism should be pursued, and more refined understanding of the neuropathology of autism will be essential to continue to build and enhance animal models in the future.