Neurotoxin Modeling of Brain Disorders — Life-long Outcomes in Behavioral Teratology

Tracy A. Doucette, R. Andrew Tasker, Doucette, Tracy A., Tasker, R. Andrew

In mammals, the period shortly before and shortly after birth is a time of massive brain growth, plasticity and maturation. It is also a time when the developing brain is exquisitely sensitive to insult, often with long-lasting consequences. Many of society's most debilitating neurological diseases arise, at least in part, from trauma around the time of birth but go undetected until later in life. For the past 15 years, we have been studying the consequences of exposure to the AMPA/kainate agonist domoic acid (DOM) on brain development in the rat. Domoic acid is a naturally occurring excitotoxin that enters the food chain and is known to produce severe neurotoxicity in humans and other adult wildlife. Our work, and that of others, however, has demonstrated that DOM is also toxic to the perinatal brain and that toxicity occurs at doses much lower than those required in adults. This raises concern about the current regulatory limit for DOM contamination that is based on data in adult animals, but has also allowed creation of a novel model of neurological disease progression. Herein, we review briefly the toxicity of DOM in adults, including humans, and describe features of the developing nervous system relevant to enhanced risk. We then review the data on DOM as a prenatal neuroteratogen and describe in detail the work of our respective laboratories to characterize the long-term behavioural and neuropathological consequences of exposure to low-dose DOM in the newborn rat.