Kainate and AMPA receptors in epilepsy: Cell biology, signalling pathways and possible crosstalk.

Epilepsy is caused when rhythmic neuronal network activity escapes normal control mechanisms, resulting in seizures. There is an extensive and growing body of evidence that the onset and maintenance of epilepsy involves alterations in the trafficking, synaptic surface expression and signalling of kainate and AMPA receptors (KARs and AMPARs). The KAR subunit GluK2 and AMPAR subunit GluA2 are key determinants of the properties of their respective assembled receptors. Both subunits are subject to extensive protein interactions, RNA editing and post-translational modifications. In this review we focus on the cell biology of GluK2-containing KARs and GluA2-containing AMPARs and outline how their regulation and dysregulation is implicated in, and affected by, seizure activity. Further, we discuss role of KARs in regulating AMPAR surface expression and plasticity, and the relevance of this to epilepsy. This article is part of the special issue on 'Glutamate Receptors - Kainate receptors'.

Changes in excitatory and inhibitory receptor expression and network activity during induction and establishment of epilepsy in the rat Reduced Intensity Status Epilepticus (RISE) model.

The RISE model is an effective system to study the underlying molecular and cellular mechanisms involved in the initiation and maintenance of epilepsy in vivo. Here we profiled the expression of excitatory and inhibitory neurotransmitter receptor subunits and synaptic scaffolding proteins in the hippocampus and temporal lobe and compared these changes with alterations in network activity at specific timepoints during epileptogenesis. Significant changes occurred in all of the ionotropic glutamate receptor subunits tested during epilepsy induction and progression and the profile of these changes differed between the hippocampus and temporal lobe. Notably, AMPAR subunits were dramatically decreased during the latent phase of epilepsy induction, matched by a profound decrease in the network response to kainate application in the hippocampus. Moreover, decreases in the GABAAß3 subunit are consistent with a loss of inhibitory input contributing to the perturbation of excitatory/inhibitory balance and seizure generation. These data highlight the synaptic reorganisation that mediates the relative hypoexcitability prior to the manifestation of seizures and subsequent hyperexcitability when spontaneous seizures develop. These patterns of changes give new insight into the mechanisms underpinning epilepsy and provide a platform for future investigations targeting particular receptor subunits to reduce or prevent seizures.