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Defining Domoic Acid Epileptic Disease

This project began in January 2009 and was completed in December 2013

Domoic acid epileptic disease, a central nervous system disorder caused by the algal toxin domoic acid (DA), first showed up in humans in a 1987 shellfish poisoning in Quebec, Canada. The disease later appeared in California sea lions as a chronic epileptic syndrome following DA poisonings. The sea lion study provided insight into unusual behaviors, brain pathology, and epidemiology. Our experimental model defines the disease and its progressive steps from poisoning to an epileptic state.

Why We Care
The long-term effects of poisoning by harmful algal bloom toxins concern us. Hundreds of sea lions showed signs of epileptic disease during time periods when no HAB events were occurring. An elderly man developed epilepsy a year after he appeared to have recovered from seizures after eating DA contaminated shellfish. Direct evidence showing epileptic disease develops months after DA poisoning was needed to provide the best science-based information to understand the linkage between short term DA poisoning and long term epileptic disease.

We promptly developed a model to demonstrate that DA poisoning weeks to months later lead to epilepsy and aggressive behavior in laboratory rats (Muha and Ramsdell 2011). Armed with an experimental model, we were ready to investigate what triggers this disease, what is happening during the silent while the disease develops and what type of brain damage causes the epilepsy and aggressive behavior to promote more effective treatment of sea lions and establish a basis for understanding this disease in humans.

What We Did
We first developed a testable model of disease progression. The model included three phases:

  1. A toxin phase, where the DA poisoning damages the brain leading to temporary seizures,
  2. A latent (dormant) phase, where most of the initial damage is repaired but other damage continues during a “silent period” with no outward signs of disease, and
  3. A disease phase, where symptoms begin to appear, and damage becomes progressively worse.

We repeated the experiment and induced the disease state in rats, followed the animals’ behavior carefully and at different times mapped damage to their brain. During the toxin phase, DA targets the region of the brain involving smell (the olfactory bulb), leading to damage of nerve contacts between special neurons involving smell (the mitral cells and granule cells). This damage excites olfactory pathways leading to short term seizures, which in turn causes more damage throughout the brain.

We determined nearly all of this damage is temporary and repaired over several weeks. However, some damage continues and becomes worse in the deep layers of the piriform cortex, a brain area where certain forms of human epilepsy are thought to originate. Damage to the piriform cortex continues regardless if the animals show only epilepsy or only aggression, suggesting each disease state has a common origin during the latent phase.

Interestingly, animals that showed aggression also had damage to the secondary olfactory cortex, a part of the brain important in social recognition by sense of smell. This additional damage can affect the ability of animals to recognize members of their social group and lead to the type of aggression typically seen in sea lions with DA disease.

Next Steps
The experimental work has opened the possibility to treat aggressive animals with a short-acting drug to promote social recognition.

This information has been disseminated broadly through both the medical and wildlife veterinary communities through a full description of the disease in humans and sea lions which is to be published in 2013.

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