The potent mGlu receptor antagonist LY341495 identifies roles for both cloned and novel mGlu receptors in hippocampal synaptic plasticity

Understanding the roles of metabotropic glutamate (mGlu) receptors has been severely hampered by the lack of potent antagonists. LY341395 (2S-2-amino-2-(1S,2S-2-carboxcyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid) has been shown to block group II mGlu receptors in low nanomolar concentrations (Kingston, A.E,, Ornstein, P.L., Wright, R.A., Johnson, B.C;., Mayne, N.G., Burnett, J.P., Belagaje, R., Wu, S., Schoepp, D.D., 1998. LY341495 is a nanomolar potent and selective antagonist at group IT metabotropic glutamate receptors. Neuropharmacology 37, 1-12) but can be used ill higher concentrations to block all hippocampal mGlu receptors, identified so far by molecular cloning (mGlu(1-5,) (7,8)). Here we have further characterised the mGlu receptor antagonist activity of LY341495 and have used this compound to investigate roles of mGlu receptors in hippocampal long-term potentiation (LTP) and long-term depression (LTD), LY341495 competitively antagonised DHPG-stimulated PI hydrolysis in AV12-664 cells expressing either human mGlu; or mGlu, receptors with K-i-values of 7.0 and 7.6 mu M, respectively. When tested against 10 mu M L-glutamate-stimulated Ca2+ mobilisation in rat mGlu, expressing CHO cells, it produced substantial or complete block at a concentration of 100 mu M. Tn rat hippocampal slices, LY341495 eliminated 30 mu M DHPG-stimulated PI hydrolysis and 100 mu M (1S,3R)-ACPD-inhibition of forskolin-stimulated cAMP formation at concentrations of 100 and 0.03 mu M respectively. In area CA1, it antagonised DHPG-mediated potentiation of NMDA-induced depolarisations and DHPG-induced long-lasting depression of AMPA receptor-mediated synaptic transmission. LY341495 also blocked NMDA receptor-independent depotentiation and setting of a molecular switch involved in the induction of LTP; effects which have previously been shown to be blocked by the mGlu receptor antagonist (S)-MCPG. These effects may therefore be due to activation of cloned mGlu receptors. In contrast, LY341495 did not affect NMDA receptor-dependent homosynaptic T-TD; an effect which may therefore be independent of cloned mGlu receptors. Finally, LY341395 failed to antagonise NMDA receptor-dependent LTP and, in area CA3. NMDA receptor-independent, mossy fibre LTP. Since in the same inputs these forms of LTP were blocked by (S)-MCPG, a novel type of mGlu receptor may be involved in their induction. (C) 1998 Elsevier Science Ltd. All rights reserved.