Kainate receptors (KARs) are involved in both NMDA receptor-independent long-term potentiation (LTP) and synaptic facilitation at mossy fibre synapses in the CA3 region of the hippocampus. However, the identity of the KAR subtypes involved remains controversial. Here we used a highly potent and selective GluK1 (formerly GluR5) antagonist (ACET) to elucidate roles of GluK1-containing KARs in these synaptic processes. We confirmed that ACET is an extremely potent GluK1 antagonist, with a Kb value of 1.4+/-0.2 nM. In contrast, ACET was ineffective at GluK2 (formerly GluR6) receptors at all concentrations tested (up to 100 microM) and had no effect at GluK3 (formerly GluR7) when tested at 1 microM. The X-ray crystal structure of ACET bound to the ligand binding core of GluK1 was similar to the UBP310-GluK1 complex. In the CA1 region of hippocampal slices, ACET was effective at blocking the depression of both fEPSPs and monosynaptically evoked GABAergic transmission induced by ATPA, a GluK1 selective agonist. In the CA3 region of the hippocampus, ACET blocked the induction of NMDA receptor-independent mossy fibre LTP. To directly investigate the role of pre-synaptic GluK1-containing KARs we combined patch-clamp electrophysiology and 2-photon microscopy to image Ca2+ dynamics in individual giant mossy fibre boutons. ACET consistently reduced short-term facilitation of pre-synaptic calcium transients induced by 5 action potentials evoked at 20-25Hz. Taken together our data provide further evidence for a physiological role of GluK1-containing KARs in synaptic facilitation and LTP induction at mossy fibre-CA3 synapses.
Dargan, S., Clarke, V., Alushin, G., Sherwood, J., NISTICO', R.G., Bortolotto, Z., et al. (2009). ACET is a highly potent and specific kainate receptor antagonist: Characterisation and effects on hippocampal mossy fibre function. NEUROPHARMACOLOGY, 56(1), 121-130.
|Tipologia:||Articolo su rivista|
|Citazione:||Dargan, S., Clarke, V., Alushin, G., Sherwood, J., NISTICO', R.G., Bortolotto, Z., et al. (2009). ACET is a highly potent and specific kainate receptor antagonist: Characterisation and effects on hippocampal mossy fibre function. NEUROPHARMACOLOGY, 56(1), 121-130.|
|Settore Scientifico Disciplinare:||Settore BIO/14|
|Revisione (peer review):||Esperti anonimi|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.neuropharm.2008.08.016|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||2009|
|Titolo:||ACET is a highly potent and specific kainate receptor antagonist: Characterisation and effects on hippocampal mossy fibre function|
|Autori:||Dargan, S; Clarke, V; Alushin, G; Sherwood, J; NISTICO', RG; Bortolotto, Z; Ogden, A; Bleakman, D; Doherty, A; Lodge, D; Mayer, M; Fitzjohn, S; Jane, D; Collingridge, G|
|Appare nelle tipologie:||01 - Articolo su rivista|