Abstract
Epilepsies affect about 4% of the population and are frequently characterized by a prolonged “silent” period before the onset of spontaneous seizures. Most current animal models of epilepsy either involve acute seizure induction or kindling protocols that induce repetitive seizures. We have developed a rat model of epilepsy that is characterized by a slowly progressing series of behavioral abnormalities prior to the onset of behavioral seizures. In the current study, we further describe an accompanying progression of cytoarchitectural changes in the hippocampal formation. Groups of male and female SD rats received serial injections of a low dose of domoic acid (0.020 mg/kg) (or vehicle) throughout the second week of life. Postmortem hippocampal tissue was obtained on postnatal days 29, 64, and 90 and processed for glial fibrillary acidic protein (GFAP), NeuN, and calbindin expression. The data revealed no significant changes on postnatal day (PND) 29 but a significant increase in hilar NeuN-positive cells in some regions on PND 64 and 90 that were identified as ectopic granule cells. Further, an increase in GFAP positive cell counts and evidence of reactive astrogliosis was found on PND 90 but not at earlier time points. We conclude that changes in cellular expression, possibly due to on-going non-convulsive seizures, develop slowly in this model and may contribute to progressive brain dysfunction that culminates in a seizure-prone phenotype.
Highlights
Domoic acid (DOM), a naturally occurring analogue of glutamate, is structurally similar to kainic acid and can be found in marine algae and several species of phytoplankton resulting in developmental neurotoxicity in multiple species
Human consumption of DOM can result in the development of temporal lobe epilepsy (TLE) [3] demonstrating that animal models of epilepsy induced by DOM are clinically relevant
Administration of low doses of DOM in neonatal rats does not produce overt toxicity or status epilepticus but results in permanent alterations in adult rat behavior that manifest as changes in cognition [17,18,19], attentional processing [20,21,22], anxiety [18, 23], seizure threshold [24], and sleep patterns [25] that are consistent with the development of temporal lobe epilepsy (TLE)
Summary
Domoic acid (DOM), a naturally occurring analogue of glutamate, is structurally similar to kainic acid and can be found in marine algae and several species of phytoplankton resulting in developmental neurotoxicity in multiple species (for review, see [1, 2]). Administration of low doses of DOM in neonatal rats does not produce overt toxicity or status epilepticus but results in permanent alterations in adult rat behavior that manifest as changes in cognition [17,18,19], attentional processing [20,21,22], anxiety [18, 23], seizure threshold [24], and sleep patterns [25] that are consistent with the development of temporal lobe epilepsy (TLE) These changes in behavior have been shown to correlate with neuropathological changes in the hippocampal formation such as mossy fiber sprouting (MFS) [17, 26] and selective loss of parvalbumin-positive GABAergic interneurons [27] that are present in both animal models of TLE produced by kainic acid [13, 28] as well as human TLE patients [29]. These multiple reports have led us to propose that low dose neonatal DOM initiates a slowly developing epileptogenic process that creates an animal model for studying the development of epilepsy and the identification of presymptomatic biomarkers of epileptogenesis (for review, see [30,31,32])
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