A HIPPOCAMPAL GLUR5 KAINATE RECEPTOR REGULATING INHIBITORY SYNAPTIC TRANSMISSION

The principal excitatory neurotransmitter in the vertebrate central ne rvous system, L-glutamate, acts on three classes of ionotripic glutama te receptors, named after the agonists AMPA a-amino-3-hydroxy-5-methyl -4-isoxalole-4-propionic acid),NMDA (N-methyl-D-aspartate) and kainate (1). The development of selective pharmacological agents has led to a detailed understanding of the physiological and pathological roles of AMPA and NMDA receptors(2-8). in contrast, the lack of selective kaina te receptor ligands has greatly hindered progress in understanding the roles of kainate receptors(9,10). Here we describe the effects of a p otent and selective agonist, ATPA o-3-(3-hydroxy-5-tert-butylisoxazol- 4-yl)propanoic acid) and a selective antagonist, LY294486 ((3SR, 4aRS, 6SR, 8aRS)-6-((((1H-tetrazol-5-yl) methyl)oxy)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylic acid), of the GluR5 subtype of kainate receptor(11). We have used these agents to show th at kainate receptors, comprised of or containing GluR5 subunits, regul ate synaptic inhibition in the hippocampus, an action that could contr ibute to the epileptogenic effects of kainate(12-17).