Animal Model of Autistic Regression: Link to Toxicant-Induced Oxidative Stress

Abstract

Kanner, in his initial case study report defining autism, concluded .... “We must, then, assume that these children have come into the world with innate inability to form the usual, biologically provided affective contact with people, just as other children come into the world with innate physical or intellectual handicaps.” Nonetheless, in at least one of his eleven cases, a period of normal development was noted, but this was followed by a period of arrested development and loss of acquired skills. Today, this scenario would be referred to as autistic regression and is thought to account for 35–40 % of all autism cases. We have developed an animal model of autistic regression characterizing functional and neuropathological deficits in mice consequent to early toxicant exposure. Further, we have administered neurotoxicants known to exert their deleterious effects through the generation of oxidative stress to mice with genetic alterations thought to render them particularly sensitive to such insult. Regardless of the types of insult, oxidative stress is believed to be a common endpoint that would contribute to the pathology of autism. Nrf2 is the major transcription regulator for redox regulation. To further test the hypothesis, we have used Nrf2 knockout mice with age-matched wild-type mice. The knockout mice engaged in fewer social play contacts with other mice. Treatment with valproic acid also resulted in a reduction in play behavior in the knockout mice. These very preliminary observations indicate that the Nrf2 KO mice may be useful in advancing our understanding of the underlying etiology of autistic regression. Collectively, these animal data suggest a role for oxidative stress underlying autistic regression.