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.

PSD-95 regulates synaptic kainate receptors at mouse hippocampal mossy fiber-CA3 synapses

“…1A). This result is consistent with a previous study showing that 2 μM ACET partly suppressed KARs-mediated currents at mossy fiber-CA3 synapse (Pinheiro et al, 2013, but see Dargan et al, 2009). In PSD-95 knockout mice, substantial GYKI-resistant slow components were observed (amplitude: to 8.7 ± 0.7% of control, charge transfer: to 18.9 ± 2.0% of control, n = 8, Fig.…”

Kainate Receptor Post-translational Modifications Differentially Regulate Association with 4.1N to Control Activity-dependent Receptor Endocytosis

“…How these modulatory systems impact synaptic signaling is less clear because gene-targeted mice lacking 4.1G and with reduced 4.1N expression exhibit no apparent deficits in NMDA receptor-dependent long term potentiation (37). AMPA and kainate receptors perform different functions in the CNS; in part, this arises from very distinct gating kinetics of postsynaptic receptors, which have important consequences on neuronal excitability, particularly during repetitive activation (38). In addition, synaptic expression is both developmentally (39) and differentially regulated by protein interactions (19,36).…”

Impaired neuronal operation through aberrant intrinsic plasticity in epilepsy

“…To test the role of KARs in the potentiation of PP-DGC firing rate induced by rMF-CT, experiments were performed in the presence of the KAR blocker UBP310 58 . We observed that UBP310 (5 µM) prevented the rMF-DGC sustained firing (rMF-CT without UBP310: 5.83 ± 0.23 Hz, n = 15 vs. with UBP310: 1.62 ± 0.26 Hz, n = 11, p = 0.00002) (Fig 3A, I) and the subsequent rMF-CT-dependent potentiation of the PP-DGC firing rate in epileptic rats (before 14 CT: 1.06 ± 0.09 Hz vs. after CT: 1 ± 0.08 Hz, n = 12, p = 0.790) (Fig 3A, B, J).…”