Antagonists of GLUK5-containing kainate receptors prevent pilocarpine-induced limbic seizures

Ilse Smolders, Zuner A. Bortolotto, Vernon R.J. Clarke, Ruth Warre, Ghous M. Khan, Michael J. O’Neill, Paul L. Ornstein, David Bleakman, Ann Marie Ogden, Brianne Weiss, James P. Stables, Ken H. Ho, Guy Ebinger, Graham L. Collingridge, David Lodge, Yvette Michotte

Research output: Contribution to journalArticlepeer-review

136 Scopus citations

Abstract

Developments in the molecular biology and pharmacology of GLUK5, a subtype of the kainate class of ionotropic glutamate receptors, have enabled insights into the roles of this subunit in synaptic transmission and plasticity. However, little is known about the possible functions of GLUK5-containing kainate receptors in pathological conditions. We report here that, in hippocampal slices, selective antagonists of GLUK5-containing kainate receptors prevented development of epileptiform activity - evoked by the muscarinic agonist, pilocarpine - and inhibited the activity when it was pre-established. In conscious rats, these GLUK5 antagonists prevented and interrupted limbic seizures induced by intra-hippocampal pilocarpine perfusion, and attenuated accompanying rises in extracellular L-glutamate and GABA. This anticonvulsant activity occurred without overt side effects. GLUK5 antagonism also prevented epileptiform activity induced by electrical stimulation, both in vitro and in vivo. Therefore, we propose that subtype-selective GLUK5 kainate receptor antagonists offer a potential new therapy for epilepsy.

Original languageEnglish (US)
Pages (from-to)796-804
Number of pages9
JournalNature neuroscience
Volume5
Issue number8
DOIs
StatePublished - Aug 2002

ASJC Scopus subject areas

  • General Neuroscience

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