Synergistic interactions between kainate and mGlu receptors regulate bouton Ca2+ signalling and mossy fibre LTP

It is currently unknown why glutamatergic presynaptic terminals express multiple types of glutamate receptors. We have addressed this question by studying both acute and long-term regulation of mossy fibre function in the hippocampus. We find that inhibition of both mGlu₁ and mGlu₅ receptors together can block the induction of mossy fibre LTP. Furthermore, mossy fibre LTP can be induced by the pharmacological activation of either mGlu₁ or mGlu₅ receptors, provided that kainate receptors are also stimulated. Like conventional mossy fibre LTP, chemically-induced mossy fibre LTP (chem-LTPm) depends on Ca²⁺ release from intracellular stores and the activation of PKA. Similar synergistic interactions between mGlu receptors and kainate receptors were observed at the level of Ca²⁺ signalling in individual giant mossy fibre boutons. Thus three distinct glutamate receptors interact, in both an AND and OR gate fashion, to regulate both immediate and long-term presynaptic function in the brain.