Selective block of postsynaptic kainate receptors reveals their function at hippocampal mossy fiber synapses

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.