title: Selective block of postsynaptic kainate receptors reveals their function at hippocampal mossy fiber synapses.
abstract: Progress in understanding the roles of kainate receptors (KARs) in synaptic integration, synaptic networks, and higher brain function has been hampered by the lack of selective pharmacological tools. We have found that UBP310 and related willardiine derivatives, previously characterized as selective GluK1 and GluK3 KAR antagonists, block postsynaptic KARs at hippocampal mossy fiber (MF) CA3 synapses while sparing AMPA and NMDA receptors. We further show that UBP310 is an antagonist of recombinant GluK2/GluK5 receptors, the major population of KARs in the brain. Postsynaptic KAR receptor blockade at MF synapses significantly reduces the sustained depolarization, which builds up during repetitive activity, and impacts on spike transmission mediated by heterosynaptic signals. In addition, KARs present in aberrant MF synapses in the epileptic hippocampus were also blocked by UBP310. Our results support a specific role for postsynaptic KARs in synaptic integration of CA3 pyramidal cells and describe a tool that will be instrumental in understanding the physiopathological role of KARs in the brain.
authors.affiliation: Interdisciplinary Institute for Neuroscience, University of Bordeaux, F-33000 Bordeaux, France.
authors.forename: Paulo S
authors.initials: PS
authors.lastname: Pinheiro
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lanore
authors.forename: Julien
authors.initials: J
authors.lastname: Veran
authors.forename: Julien
authors.initials: J
authors.lastname: Artinian
authors.forename: Christophe
authors.initials: C
authors.lastname: Blanchet
authors.forename: Valérie
authors.initials: V
authors.lastname: Crépel
authors.forename: David
authors.initials: D
authors.lastname: Perrais
authors.forename: Christophe
authors.initials: C
authors.lastname: Mulle
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000378:metabolism / Q000503:physiopathology*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019599:Mossy Fibers, Hippocampal / Q000502:physiology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D018092:Kainic Acid Receptors / Q000378:metabolism*; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D018092:Kainic Acid Receptors