Paradoxical anti-epileptic effects of a GluR5 agonist of kainate receptors.
Kainate generates in adult hippocampal neurons a seizure but also a massive excitation of interneurons and a dramatic increase of the inhibitory drive that impinges on principal cells. This "overinhibition" is largely mediated by GluR5-containing kainate receptors that are enriched on interneurons. Here, using the neonatal intact hippocampus in vitro and the triple chamber, we first show that this mechanism is fully operative in neonatal neurons. We then report that application to one hippocampus of (RS)-2-amino-3-(5-tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid-a relatively selective agonist of GluR5 containing kainate receptors-depresses the propagation of seizure generated in the opposite hippocampus by a convulsive agent. We conclude that the selective excitation of interneurons by GluR5-containing kainate receptor agonists opens a new therapeutic approach for the epilepsies.
Khalilov
Ilgam
I
Institut de Neurobiologie de la Méditerranée, Institut National de la Santé et de la Recherche Médicale, U29, Marseille, France.
Hirsch
June
J
Cossart
Rosa
R
Ben-Ari
Yehezkel
Y
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology; D000927:Anticonvulsants / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D007555:Isoxazoles / Q000494:pharmacology*; D009433:Neural Inhibition; D011422:Propionates / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018092:Kainic Acid Receptors / Q000819:agonists*; D012640:Seizures / Q000503:physiopathology / Q000517:prevention & control
D000927:Anticonvulsants; D007555:Isoxazoles; D011422:Propionates; D018092:Kainic Acid Receptors; C081662:alpha-amino-3-hydroxy-5-tert-butyl-4-isoxazolepropionate