Trends in Neurosciences
Volume 23, Issue 11, 1 November 2000, Pages 580-587
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Review
Kainate, a double agent that generates seizures: two decades of progress

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Abstract

Studies using kainate, an excitatory amino acid extracted from a seaweed, have provided major contributions to the understanding of epileptogenesis. Here we review pioneering and more recent studies aimed at determining how kainate generates seizures and, in particular, how inhibition is altered during seizures. We focus on target and subunit-specific effects of kainate on hippocampal pyramidal neurons and interneurons that lead to an excitation of both types of neurons and thus to the parallel increase of glutamatergic and GABAergic spontaneous currents. We propose that kainate excites all its targets, the net consequence depending on the level of activity of the network.

Section snippets

The kainate experimental animal model of TLE

Studies performed two decades ago have shown that systemic or intracerebral injections of kainate cause epileptiform seizures in the CA3 region of the hippocampus. These seizures propagate to other limbic structures and are followed by a pattern of cell loss that is similar to that seen in patients suffering from TLE1., 2..

CA3 pyramidal neurons are indeed amongst the most responsive neurons to kainate in the brain, because they readily degenerate following local or distal injections of kainate.

Activation of GluR6-containing kainate receptors at mossy fiber synapses located on CA3 pyramidal neurons

Repetitive electrical stimulation of the mossy fiber pathway generates slow EPSCs in CA3 pyramidal neurons that are mediated by kainate receptors and not AMPA receptors because they are resistant to the selective AMPA receptor antagonist GYKI53655 (22., 23.). The mossy fiber synapses are located close to the soma of pyramidal neurons and should therefore generate EPSCs that will efficiently propagate to the cell body and its intracellular machinery. These EPSCs are not generated in CA1

Activation of GluR5 containing receptors located on interneurons

Two recent studies have shown that applications of low concentrations (submicromolar) of kainate in the presence of selective NMDA and AMPA receptors antagonists produce a massive long-lasting depolar-ization of CA1 interneurons and a powerful and sustained barrage of action potentials13., 24.. As expected, the consequence of this strong excitation of interneurons is an increase of the spontaneous inhibition recorded in CA1 pyramidal neurons (Fig. 2); indeed, an eightfold increase of the

Presynaptic effects of kainate on the release of GABA

The observation that kainate enhances spontaneous GABAA-mediated inhibition was unexpected because intuitively epileptogenesis should be associated with a reduction of GABA-mediated inhibition. In fact, a collapse of inhibition has been repeatedly suggested to underlie the epileptogenic effects of kainate11., 14., 30.. Two parameters have been examined in detail: evoked GABA-mediated IPSCs and miniature TTX-insensitive IPSCs. However, in contrast to the clear cut effects of kainate on tonic

Other non-direct effects of kainate

Kainate has additional effects that might enhance or reduce the excitability of pyramidal neurons. Although these early studies were carried out before the availability of selective AMPA receptor antagon-ists, the effects observed with low concentrations of kainate were mediated by kainate and not AMPA receptors because only kainate receptors are activated with submicromolar concentrations13. The following effects deserve emphasis.

(1) Low concentrations of kainate (100–200 nm) facilitate the

Concluding remarks

Kainate acts as a ‘double-agent’ controlling the hippocampal network activity via the activation of an heterogeneous network of kainate receptors differentially distributed among inhibitory interneurons and excitatory pyramidal cells. Hence, kainate in the nanomolar range generates seizures in CA3 at least in part through the activation of GluR6-containing receptors localized postsynaptically at mossy fiber synapses on pyramidal cells. Kainate, at similar low concentrations, massively increases

Acknowledgements

The authors are indebted to C. Bernard, M. Esclapez and J.C. Hirsch for their major contribution to most of the results reviewed in this paper and for their helpful comments on the manuscript.

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