Role of GluK1 kainate receptors in seizures, epileptic discharges, and epileptogenesis.

Abstract

Kainate receptors containing the GluK1 subunit have an impact on excitatory and inhibitory neurotransmission in brain regions, such as the amygdala and hippocampus, which are relevant to seizures and epilepsy. Here we used 2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid (ATPA), a potent and selective agonist of kainate receptors that include the GluK1 subunit, in conjunction with mice deficient in GluK1 and GluK2 kainate receptor subunits to assess the role of GluK1 kainate receptors in provoking seizures and in kindling epileptogenesis. We found that systemic ATPA, acting specifically via GluK1 kainate receptors, causes locomotor arrest and forelimb extension (a unique behavioral characteristic of GluK1 activation) and induces myoclonic behavioral seizures and electrographic seizure discharges in the BLA and hippocampus. In contrast, the proconvulsant activity of systemic AMPA, kainate, and pentylenetetrazol is not mediated by GluK1 kainate receptors, and deletion of these receptors does not elevate the threshold for seizures in the 6 Hz model. ATPA also specifically activates epileptiform discharges in BLA slices in vitro via GluK1 kainate receptors. Olfactory bulb kindling developed similarly in wild-type, GluK1, and GluK2 knock-out mice, demonstrating that GluK1 kainate receptors are not required for epileptogenesis or seizure expression in this model. We conclude that selective activation of kainate receptors containing the GluK1 subunit can trigger seizures, but these receptors are not necessary for seizure generation in models commonly used to identify therapeutic agents for the treatment of epilepsy.

• Authors: Brita Fritsch, Janine Reis, Maciej Gasior, Rafal M Kaminski, Michael A Rogawski
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 34 Issue 17 Pg. 5765-75 (Apr 23 2014) ISSN: 1529-2401 [Electronic] United States
• PMID: 24760837 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• Excitatory Amino Acid Agonists
• Gluk1 kainate receptor
• Gluk2 kainate receptor
• Isoxazoles
• Propionates
• Receptors, Kainic Acid
• alpha-amino-3-hydroxy-5-tert-butyl-4-isoxazolepropionate

Topics

• Amygdala (drug effects, metabolism, physiopathology)
• Animals
• Epilepsy (metabolism, physiopathology)
• Excitatory Amino Acid Agonists (pharmacology)
• Hippocampus (drug effects, metabolism, physiopathology)
• Isoxazoles (pharmacology)
• Mice
• Mice, Knockout
• Propionates (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Kainic Acid (agonists, genetics, metabolism)
• Seizures (metabolism, physiopathology)