Differential effect of the mGlu5 receptor positive allosteric modulator ADX-47273 on early and late hippocampal LTP

Abstract

Conflicting findings are reported in the literature about the involvement of the mGlu5 receptor in hippocampal long-term potentiation (LTP), which might be a consequence of different sub-types of LTP induced by the investigators due to the specific experimental conditions used. A comparable controversy came up in the past concerning the influence of different experimental conditions on the involvement of L-type voltage dependent calcium channels (L-VDCCs) and NMDA receptors in hippocampal LTP. In this study, two stimulation protocols with otherwise identical conditions were used to probe modulatory effects of mGlu5 receptor activation in NMDA receptor and L-VDCCs dependent CA1 LTP: weak high frequency stimulation (20 stimuli at 100 Hz) to induce early LTP and repeated strong high frequency stimulation (3 times 100 stimuli at 100 Hz with 5 min interval) to induce late LTP, which - in contrast to early LTP - was shown to be protein-synthesis dependent. Using the NMDA receptor antagonist MK-801 and the L-type calcium channel blocker nifedipine, early LTP was shown to be dependent on NMDA receptors only, whereas late LTP was demonstrated to be dependent on NMDA receptors and L-VDCCs in about equal parts. Moreover, late LTP, but not early LTP, was increased by the mGlu5 receptor positive allosteric modulator ADX-47273, indicating that artificial augmentation of mGlu5 receptor activation by endogenous glutamate may boost the protein-synthesis dependent form of LTP but not the protein-synthesis independent form.