Session 5: Environmental Influences as Etiologic Factors in Autism
Kenneth. Reuhl, Neurotoxicology Laboratories, UMDNJ-Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ
The proper development of the CNS depends upon the temporally and spatially-regulated expression of cell adhesion molecules (CAMs), several families of membrane proteins which are particularly important for pathway development, establishment of appropriate synaptic partnerships, and modifications of synaptic contacts during learning and following injury (i.e., synaptic plasticity). Failure of CAMs to function appropriately during development results in a spectrum of deficits ranging from gross malformations to subtle psychomotor retardation.
Developmental exposure to toxic heavy metals is highly effective in disrupting CAM expression. Methylmercury (MeHg), lead and trimethyltin have been shown to selectively perturb expression of the180 kDa isoform of the neural cell adhesion molecule. NCAM180 is particularly heavily expressed on the post-synaptic membrane of neurons that undergo synaptic remodeling during learning, memory and acquisition of non-stereotypic behaviors. Toxic metals impair expression/function of NCAM180 by inhibiting the golgi-sialyltransferase mediated, post-translational addition of polysialic acids to the extracellular domain and/or by activating proteases that amputate the linkage of NCAM to the cytoskeleton. Disturbance of NCAM180 expression during critical developmental stages results in synaptic dysgenesis within the cerebellar and limbic pathways, and seriously impairs the ability of synapses to remodel in response to standardized learning paradigms. These effects on the regulation of NCAM180 are persistent and may be detected biochemically and immunochemically months after cessation of metal exposure. Co-administration of serotonin or NMDA agonists with the toxic metal partially prevents the alterations of NCAM180 and the deleterious effects on synaptic structure. Such treatments also appear to enhance NCAM180 expression by neurons exposed to toxic metals earlier in development.
The relationship of environmental agents to autism and related diseases is unclear; however, there is growing evidence that genetic and environmental factors may interact to increase the incidence of autism. There is strong evidence to suggest that environmental chemicals may disturb CAMs and several studies have reported decreased expression of serum NCAM in patients with autism. The regulation of synaptic CAMs, particularly NCAM180, represents a control point for synaptic behavior and an attractive target for developmental effects exerted by toxic metals.
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