In contrast, others (Khalilov et al., 2002) have indicated a potential for GluK1

agonists Venetoclax molecular weight as antieplieptic based on the overinhibition largely mediated by GluK1-containing receptors, which are enriched in hippocampal interneurons. The muscarinic agonist pilocarpine is used as a standard model to generate epileptiform activity in order to evaluate the potential of anticonvulsant drugs (cf. Smolders et al., 2002 and references therein). One of the advantages of this model is that it does not involve direct stimulation of KARs, thereby allowing the evaluation of the contribution of tonic KAR activation by ambient glutamate to the epileptic phenomena. It is likely that multiple mechanisms may account for the involvement of KARs in epilepsy. It is possible that the glutamate released due to circuit hyperactivity may provoke both tonic activation

of CA3 neurons and KAR-mediated depression of synaptic inhibition. These two actions NVP-BGJ398 research buy would be sufficient to generate a drastic imbalance between excitation and inhibition, leading to hippocampal seizures. A similar mechanism has been invoked in the amygdala to account for the therapeutic effects of topiramate (Braga et al., 2009), an approved antiepileptic medicine. A linkage study of 20 families found a significant excess of the Grik1 tetranucleotide polymorphism (nine “AGTA” repeats) in members of families affected by idiopathic juvenile absence epilepsy ( Sander et al., 1997). This allelic variant of Grik1 probably confers susceptibility to juvenile absence epilepsy, when superimposed on a background of strong polygenic effects. The tetranucleotide polymorphism maps to the noncoding region of the gene, close to regulatory sequences, and although it does not seem to affect receptor

structure ( Izzi et al., 2002), it could alter gene expression. However, as there is no evidence of this to date, this association may also be due to a hypothetical epilepsy gene in this region in linkage disequilibrium with Grik1 tetranucleotide repeats ( Lucarini et al., 2007). Despite all the evidence linking KARs to epilepsy, to our knowledge no antiepileptic drugs have been developed to date based on KAR antagonists. KARs are others expressed strongly in DRG cells and dorsal horn neurons, pointing to a specific role for these receptors in sensory transmission and pain. Indeed, KARs were targeted as potential elements involved in pain transmission and kainate was demonstrated to depolarize primary afferents (Agrawal and Evans, 1986). Moreover, a pure population of KARs was initially isolated from DRG neurons that are likely to be C fiber nociceptors (Huettner, 1990). Molecular and electrophysiological characterization of these neurons led us to conclude that these DRG KARs are made up of heteromeric GluK1 and GluK5 subunits (Sommer et al., 1992, Bahn et al., 1994 and Rozas et al.