Abstracts

Rationale: Harmful blooms of domoic acid-producing algae are a growing problem in oceans worldwide. Domoic acid is a potent glutamate receptor agonist that can cause status epilepticus and temporal lobe epilepsy in adult humans and other species. Unrecognized dietary exposure to low doses in pregnant women has been hypothesized to damage the fetal hippocampus and initiate temporal lobe epileptogenesis. A mouse study provided supportive evidence, but spontaneous seizures were not observed. Methods: In Experiment One, the previous study’s in utero domoic acid treatment protocol was replicated, including use of the CD-1 strain, except afterward, mice were video-monitored for convulsive seizures 9 hours/day every day from two to six months old. To further test the hypothesis in Experiment Two, a higher dose of domoic acid (1.2 mg/kg) was administered to pregnant FVB mice. FVB mice have a lower seizure threshold, and some female FVB mice spontaneously develop epilepsy. Female offspring were monitored for one-month-long periods with continuous telemetric video and bilateral hippocampal recording at ages of one to twelve months old. At the end of seizure monitoring, mice were evaluated for pathological evidence of temporal lobe epilepsy. Results: In Experiment One, none of the CD-1 mice treated in utero with vehicle (n=10) or domoic acid (n=30) was observed to experience spontaneous convulsive seizures. In Experiment Two, a similar proportion of vehicle- (12/24) and domoic acid-treated female FVB mice (10/26) spontaneously developed epilepsy, beginning in the fourth month of life. Average seizure frequencies (0.82-0.95 seizures/day) and durations (45-46 seconds) were similar in both groups. None of the eight male FVB mice (8-11 months old) developed epilepsy. None of the mice in Experiment One or Two displayed hilar neuron loss or mossy fiber sprouting, which was evident in positive-control CD-1 and FVB mice after pilocarpine-induced status epilepticus. Average seizure frequency was 5X higher in pilocarpine-treated FVB mice (5.0 seizures/day) than in spontaneoulsy epileptic FVB mice. Conclusions: These findings do not support the hypothesis that in utero exposure to domoic acid causes temporal lobe epilepsy to develop later in life. However, results provide more complete characterization of spontaneous epilepsy in female FVB mice. Funding: Supported by NSF and NIH (Office of the Director and NIEHS).