Hippocampal changes in developing postnatal mice following intrauterine exposure to domoic acid

Abstract

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.

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“…Given the recognized neuroexcitatory effects of DA via glutamate receptors, the observed behavioral dysfunction is perhaps not surprising, however, specific mechanisms for these and other effects, particularly including morphological abnormalities, have not been clarified. That said, observed behavioral effects of DA in zebrafish embryos parallel those reported for rodent models (Xi et al, 1997;Doucette et al, 2000) that specifically indicate structural changes in the hippocampus of DA-exposed neonatal rats (Dakshinamurti et al, 1993).…”

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“…It has been discovered that even intrauterine exposure to domoic acid can induce damage to hippocampal CA3 and dentate nucleus in the progeny as noticed in AD patients with no overt clinical seizure activity. 29 Histopathological evidence indicates that in addition to neurons, the astrocytes are also injured as consequence of domoic acid toxicity. Furthermore, the effect of domoic acid has been confirmed in cultured primary astrocytes from the hippocampus and the brain stem.…”

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“…The mechanism of action is that DA promotes an increase in the level of excitatory tone between neuronal synapses in the brain [38], an imbalance that favors neuronal excitation over inhibition. When DA binds to neuronal glutamate receptors, the neurons become hyper-excitable.…”

“…Most previous studies have focused on the influences of DA exposure on the hippocampus because DA exposure is epileptogenic [38]. However, prenatal exposure to DA affects the development of cortical neurocircuits that are critical for the regulation of social behavior, such as the anterior cingulate cortex (ACC) [78], which plays a central role in empathic processing [79,80], and the prefrontal cortex (PFC), which moderates sensory motor gating and the regulation of social behavior.…”