Domoic acid-induced hippocampal CA1 hyperexcitability independent of region CA3 activity

Abstract

Domoic acid (DOM) is a potent agonist of AMPA and kainic acid (KA) receptors in the CNS and is known to produce seizures acutely, and lasting excitotoxic damage in several brain regions. While the excitotoxic effects of DOM are well documented, its seizurogenic properties are less clear. In this study, we assessed the acute effects of DOM and KA in region CA1 of intact rat hippocampal slices (CA3-on) and in slices lacking region CA3 (CA3-off). Orthodromic Schaffer collateral-evoked CA1 field potentials (population spikes and somal EPSP's) were monitored during DOM and KA (10–500 nM) administration. In CA3-off slices both KA and DOM produced immediate increases in CA1 population spike amplitude. With prolonged exposure, lasting dose-dependent reductions in spike amplitude and EPSP slope were observed, possibly due to depolarising conduction block following excessive AMPA/KA receptor activation; DOM was several-fold more potent than KA in this regard. Population spike threshold did not vary with DOM, but in CA3-on slices a dose-dependent steepening of the I/O curve and increase in maximum spike amplitude was seen. CA1 hyperexcitability, as evidenced by the appearance of prominent second and third population spikes, was equivalently increased across a range of DOM concentrations in both CA3-on and CA3-off slices and, in general, DOM-induced CA1 hyperexcitability was not enhanced by the presence of CA3 for any of the other variables assessed in this study. These findings show that DOM directly promotes neuronal hyperactivity in region CA1, presumably due to tonic AMPA and/or KA-receptor mediated depolarization, and further suggests that DOM-induced hyperactivity in the recurrently networked, AMPA/KA-receptor rich region CA3 does not contribute to the onset and spread of limbic seizures during relatively mild DOM intoxication.