Dakshinamurti K, Sharma S K, Sundaram M, Watanabe T
Department of Biochemistry and Molecular Biology, University of Manitoba, Winnipeg, Canada.
J Neurosci. 1993 Oct;13(10):4486-95. doi: 10.1523/JNEUROSCI.13-10-04486.1993.
Domoic acid (0.6 mg/kg) was injected intravenously through the caudal vein in pregnant female mice on the 13th day of gestation and EEG was monitored in the developing progeny during postnatal days 10-30. No clinical seizure activity was observed during this period. However, these mice demonstrated generalized electrocortical inhibition associated with diffuse spike and wave activity in their basal EEG records. Intrauterine domoic acid-exposed (IUD) mice had significantly reduced seizure thresholds to an additional dose of domoic acid, given postnatally. At the light microscopic level, hippocampus of IUD mice exhibited age related developmental neurotoxicity. No cellular damage was observed on postnatal day 1. On day 14, severe neuronal damage was observed in the hippocampal CA3 and dentate gyrus regions. On day 30, in addition to CA3 and dentate gyrus, CA4 was also involved. Brain regional GABA levels were significantly reduced and glutamate levels increased in IUD mice. Kainate receptor binding to hippocampal synaptosomal membranes from IUD mice at 30 d of age was significantly increased. There was also an enhanced 45Ca influx into cortical and hippocampal slices of these mice. These findings suggest that intrauterine exposure to domoic acid can induce hippocampal excitotoxicity by increasing the neuronal calcium influx through kainate receptor activation. Histological changes suggest progressive hippocampal damage in IUD mice, but without overt clinical seizures.
在妊娠第13天，通过尾静脉向怀孕的雌性小鼠静脉注射软骨藻酸（0.6毫克/千克），并在出生后第10 - 30天监测发育中的后代的脑电图。在此期间未观察到临床癫痫发作活动。然而，这些小鼠在其基础脑电图记录中表现出与弥漫性棘波和慢波活动相关的全身性皮质抑制。宫内暴露于软骨藻酸（IUD）的小鼠对出生后给予的额外剂量的软骨藻酸的癫痫发作阈值显著降低。在光学显微镜水平上，IUD小鼠的海马体表现出与年龄相关的发育性神经毒性。出生后第1天未观察到细胞损伤。在第14天，在海马体CA3和齿状回区域观察到严重的神经元损伤。在第30天，除了CA3和齿状回外，CA4也受到影响。IUD小鼠脑区的GABA水平显著降低，谷氨酸水平升高。30日龄IUD小鼠海马突触体膜上的红藻氨酸受体结合显著增加。这些小鼠的皮质和海马切片中45Ca内流也增强。这些发现表明，宫内暴露于软骨藻酸可通过红藻氨酸受体激活增加神经元钙内流，从而诱导海马兴奋性毒性。组织学变化表明IUD小鼠海马体有进行性损伤，但无明显临床癫痫发作。
